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Pulmonary fibrosis involves various types of immune cells and soluble mediators, including TGF‐β and IL‐35, a recently identified heterodimeric cytokine that belongs to the IL‐12 cytokine family. However, the effect of regulatory IL‐35 may play an important role in fibrotic diseases. The aim of this paper is to explore the immunoregulatory role of IL‐35 in the development of fibrosis in interstitial lung disease (ILD). To gain a better understanding of this issue, the concentrations of IL‐35 and different profibrotic cytokines in fibrotic (F‐ILD) and non‐fibrotic (NF‐ILD) patients by ELISA were compared to that of intracellular IL‐35 and IL‐17 on CD4+ T cells stimulated in the presence of BAL or with different ratios of recombinant IL‐35 (rIL‐35) and TGF‐β (rTGF‐β), which were evaluated by flow cytometry. We observed that BAL concentration of IL‐35 was lower in F patients (p < 0.001) and was negatively correlated with concentrations of TGF‐β (p < 0.001) and IL‐17 (p < 0.001). In supplemented cell cultures, BAL from NF but not F patients enhanced the percentage of IL‐35 + CD4+ T (p < 0.001) cells and decreased the percentage of IL‐17 + CD4+ T cells (p < 0.001). The percentage of IL‐35 + CD4+ T cells correlated positively with BAL concentration of IL‐35 (p = 0.02), but correlated negatively with BAL concentrations of IL‐17 (p = 0.007) and TGF‐β (p = 0.01). After adjusting the concentrations of recombinant cytokines to establish a TGF‐β: IL‐35 ratio of 1:4, an enhanced percentage of IL‐35 + CD4+ T cells (p < 0.001) but a decreased percentage of IL‐17 + CD4+ T cells (p < 0.001) was observed. After adding recombinant IL‐35 to the BAL from F patients until a 1:4 ratio of TGF‐β: IL‐35 was reached, a significantly increased percentage of IL‐35 + CD4+ T cells (p < 0.001) and a decreased percentage of IL‐17 + CD4+ T cells (p = 0.003) was found. These results suggest that IL‐35 may induce an anti‐fibrotic response, regulating the effect of TGF‐β and the inflammatory response on CD4+ T cells. In addition, the TGF‐β: IL‐35 ratio in BAL has been shown to be a potential biomarker to predict the outcome of F patients with ILD. [ABSTRACT FROM AUTHOR]

Background: Prediction of T cell immunogenicity is a topic of considerable interest, both in terms of basic understanding of the mechanisms of T cells responses and in terms of practical applications. HLA binding affinity is often used to predict T cell epitopes, since HLA binding affinity is a key requisite for human T cell immunogenicity. However, immunogenicity at the population it is complicated by the high level of variability of HLA molecules, potential other factors beyond HLA as well as the frequent lack of HLA typing data. To overcome those issues, we explored an alternative approach to identify the common characteristics able to distinguish immunogenic peptides from non-recognized peptides. Methods: Sets of dominant epitopes derived from peer-reviewed published papers were used in conjunction with negative peptides from the same experiments/donors to train neural networks and generate an “immunogenicity score.” We also compared the performance of the immunogenicity score with previously described method for immunogenicity prediction based on HLA class II binding at the population level. Results: The immunogenicity score was validated on a series of independent datasets derived from the published literature, representing 57 independent studies where immunogenicity in human populations was assessed by testing overlapping peptides spanning different antigens. Overall, these testing datasets corresponded to over 2,000 peptides and tested in over 1,600 different human donors. The 7-allele method prediction and the immunogenicity score were associated with similar performance [average area under the ROC curve (AUC) values of 0.703 and 0.702, respectively] while the combined methods reached an average AUC of 0.725. This increase in average AUC value is significant compared with the immunogenicity score (p = 0.0135) and a strong trend toward significance is observed when compared to the 7-allele method (p = 0.0938). The new immunogenicity score method is now freely available using CD4 T cell immunogenicity prediction tool on the Immune Epitope Database website ( http://tools.iedb.org/CD4episcore ). Conclusion: The new immunogenicity score predicts CD4 T cell immunogenicity at the population level starting from protein sequences and with no need for HLA typing. Its efficacy has been validated in the context of different antigen sources, ethnicities, and disparate techniques for epitope identification. [ABSTRACT FROM AUTHOR]

In this paper, the Pseudospectral Legendre (PL) method is presented to approximate the solution of the HIV infection model of CD4+T cells. The method is based on the Lagrangian interpo- lation and the zeros of Legendre polynomial. Using the proposed method, the given system of three differential equations is converted into a system of algebraic equations. By solving the system of the algebraic equations, the unknown coefficients are computed and then the approximate solutions are obtained. The main aim of this paper is to demonstrate the PL method, and a comparison is made with the existing methods in the literature. [ABSTRACT FROM AUTHOR]

In recent decades, AIDS has been one of the main challenges facing the medical community around the world. Due to the large human deaths of this disease, researchers have tried to study the dynamic behaviors of the infectious factor of this disease in the form of mathematical models in addition to clinical trials. In this paper, we study a new mathematical model in which the dynamics of CD 4 + T-cells under the effect of HIV-1 infection are investigated in the context of a generalized fractal-fractional structure for the first time. The kernel of these new fractal-fractional operators is of the generalized Mittag-Leffler type. From an analytical point of view, we first derive some results on the existence theory and then the uniqueness criterion. After that, the stability of the given fractal-fractional system is reviewed under four different cases. Next, from a numerical point of view, we obtain two numerical algorithms for approximating the solutions of the system via the Adams-Bashforth method and Newton polynomials method. We simulate our results via these two algorithms and compare both of them. The numerical results reveal some stability and a situation of lacking a visible order in the early days of the disease dynamics when one uses the Newton polynomial. [ABSTRACT FROM AUTHOR]

This paper is devoted to the study of the stability of a CD 4 + T cell viral infection model with diffusion. First, we discuss the well-posedness of the model and the existence of endemic equilibrium. Second, by analyzing the roots of the characteristic equation, we establish the local stability of the virus-free equilibrium. Furthermore, by constructing suitable Lyapunov functions, we show that the virus-free equilibrium is globally asymptotically stable if the threshold value ℛ 0 ≤ 1 ; the endemic equilibrium is globally asymptotically stable if ℛ 0 > 1 and d u ∗ − δ w ∗ ≥ 0. Finally, we give an application and numerical simulations to illustrate the main results. [ABSTRACT FROM AUTHOR]

In this paper, we consider an improved Human T-lymphotropic virus type I (HTLV-I) infection model with the mitosis of CD4+ T cells and delayed cytotoxic T-lymphocyte (CTL) immune response by analyzing the distributions of roots of the corresponding characteristic equations, the local stability of the infection-free equilibrium, the immunity-inactivated equilibrium, and the immunity-activated equilibrium when the CTL immune delay is zero is established. And we discuss the existence of Hopf bifurcation at the immunity-activated equilibrium. We define the immune-inactivated reproduction ratio R0 and the immune-activated reproduction ratio R1. By using Lyapunov functionals and LaSalle's invariance principle, it is shown that if R0 < 1, the infection-free equilibrium is globally asymptotically stable; if R1 < 1 < R0, the immunityinactivated equilibrium is globally asymptotically stable; if R1 > 1, the immunity-activated equilibrium is globally asymptotically stable when the CTL immune delay is zero. Besides, uniform persistence is obtained when R1 > 1. Numerical simulations are carried out to illustrate the theoretical results. [ABSTRACT FROM AUTHOR]

CD28 and CD80/86 are crucial co-stimulatory molecules for the T cell activation. Previous study illustrated that CD28 and CD80/86 present on T cells and antigen-presenting cells in flounder (Paralichthys olivaceus), respectively. The co-stimulatory molecules were closely associated with cell immunity. In this paper, recombinant protein of flounder CD80/86 (rCD80/86) and phytohemagglutinin (PHA) were added to peripheral blood leukocytes (PBLs) in vitro. Lymphocytes were significantly proliferated with CFSE staining, and the proportion of CD4+ and CD28+ lymphocytes significantly increased. In the meantime, genes related to the CD28-CD80/86 signaling pathway or T cell markers were significantly upregulated (p < 0.05). For further study, the interaction between CD80/86 and CD28 was confirmed. The plasmid of CD28 (pCD28-FLAG and pVN-CD28) or CD80/86 (pVC-CD80/86) was successfully constructed. In addition, pVN-ΔCD28 without the conserved motif "TFPPPF" was constructed. The results showed that bands of pCD28-FLAG bound to rCD80/86 were detected by both anti-FLAG and anti-CD80/86. pVN-CD28 complemented to pVC-CD80/86 showing positive fluorescent signals, and pVN-ΔCD28 failed to combine with pVC-CD80/86. The motif "TFPPPF" in CD28 played a crucial role in this linkage. These results indicate that CD28 and CD80/86 molecules interact with each other, and their binding may modulate T lymphocytes immune response in flounder. This study proved the existence of CD28-CD80/86 signaling pathway in flounder. • RCD80/86 and PHA induced lymphocyte proliferation and proportion of CD4+ cells in flounder. • RCD80/86 and PHA upregulated the expression of B7-CD28 signaling pathway genes, T cell markers, and cytokines. • PCD28-FLAG bound to rCD80/86, and pVN-CD28 complemented to pVC-CD80/86 in vitro. • Motif of "TFPPPF" in CD28 plays crucial role in the interaction between CD28 and CD80/86. [ABSTRACT FROM AUTHOR]

The mechanisms by which the number of memory CD8 T cells is stably maintained remains incompletely understood. It has been postulated that maintaining them requires help from CD4 T cells, because adoptively transferred memory CD8 T cells persist poorly in MHC class II (MHCII)-deficient mice. Here we show that chronic interferon-γ signals, not CD4 T cell-deficiency, are responsible for their attrition in MHCII-deficient environments. Excess IFN-γ is produced primarily by endogenous colonic CD8 T cells in MHCII-deficient mice. IFN-γ neutralization restores the number of memory CD8 T cells in MHCII-deficient mice, whereas repeated IFN-γ administration or transduction of a gain-of-function STAT1 mutant reduces their number in wild-type mice. CD127high memory cells proliferate actively in response to IFN-γ signals, but are more susceptible to attrition than CD127low terminally differentiated effector memory cells. Furthermore, single-cell RNA-sequencing of memory CD8 T cells reveals proliferating cells that resemble short-lived, terminal effector cells and documents global downregulation of gene signatures of long-lived memory cells in MHCII-deficient environments. We propose that chronic IFN-γ signals deplete memory CD8 T cells by compromising their long-term survival and by diverting self-renewing CD127high cells toward terminal differentiation. Memory CD8+ T cells persist poorly in MHCII-deficient mice. Here the authors show that this CD8+ T cell attrition is not caused by a lack of CD4+ T cell help, as previously proposed, but by chronic IFN-γ signals derived from endogenous colonic CD8+ T cells. [ABSTRACT FROM AUTHOR]

In this paper, we report the development of a label-free biosensor, based on surface plasmon resonance, for real-time monitoring of captured human CD4+T-cells, and their dynamic cytokine production upon specific antigen stimulation. Microarrays of CD4+T-cells, and interferon gamma (IFN-γ) specific antibody (Ab) spots were printed side by side onto the poly(OEGMA-co-HEMA) matrix. The placement of CD4+ T-cells near the anti IFN-γ Ab-coated spots ensured a high local concentration of secreted IFN-γ for detection. We have demonstrated that this approach enables the detection of tuberculosis (TB) infection in clinical samples, with an overall sensitivity of 85.5% and an overall specificity of 97.7%. [ABSTRACT FROM AUTHOR]

Interleukin-2 receptor (IL-2R), as the specific ligand of interleukin-2 (IL-2), binds to IL-2 and transmits signals and then can induce the proliferation of T lymphocytes in mammals. In this paper, the subunit of IL-2R in flounder (Paralichthys olivaceus), interleukin-2 receptor subunit gamma (IL-2Rγ) was cloned, and polyclonal antibodies (Abs) against its extracellular region were produced, then the expression of flounder IL-2Rγ (fIL-2Rγ) at transcriptional and cellular levels were characterized. Moreover, the interaction of flounder IL-2 (fIL-2) with fIL-2Rγ was investigated, and the variations on CD4+/IL-2Rγ+ cells in flounder after treatment with recombinant IL-2 (rIL-2), anti-IL-2Rγ Abs were detected, respectively. The results showed that fIL-2Rγ protein had a typical fibronectin type III (FN3) domain. The Abs could specifically recognize native fIL-2Rγ molecules at 39.9 kDa. FIL-2Rγ was localized on both T and B lymphocytes, and the percentages of CD4+/IL-2Rγ+ and IgM+/IL-2Rγ+ lymphocytes were high in spleen. In addition, pBiFC-VN173-IL-2Rγ plasmids could bind to pBiFC-VC155-IL-2 plasmids. The percentage of CD4+/IL-2Rγ+ lymphocytes was significantly decreased after blocking with anti-IL-2Rγ Abs both in vivo and in vitro. In the meantime, four T cell markers genes and six IL-2-IL-2R pathway genes were down-regulated in anti-IL-2Rγ Abs group. These results first demonstrated that fIL-2Rγ molecules were expressed on both T and B lymphocytes in flounder, and the bond between fIL-2Rγ and fIL-2 activated the CD4 T lymphocytes. This study gave a new sight into the exploration of IL-2R function on T lymphocytes proliferation in fish. • IL-2Rγ mRNA was highly expressed in peripheral blood leukocytes, spleen and head kidney in flounder. • IL-2Rγ molecules were localized on both T and B lymphocytes in flounder. • Flounder IL-2 could bind to flounder IL-2Rγ. • The addition of recombinant IL-2 significantly increased the percentage of CD4+/IL-2Rγ+ lymphocytes at 72 h. [ABSTRACT FROM AUTHOR]

In this paper, the authors consider a four-compartmental HIV epidemiological model, which describes the interaction between HIV virus and two target cells, CD4 T cells and macrophages in vivo. It is proved that the bilinear incidence can cause the backward bifurcation, where a locally asymptotically stable disease-free equilibrium co-exists with a locally asymptotically stable endemic equilibrium when the basic reproduction number (R0) is less than unity. It is shown that a sequence of Hopf bifurcations occur at the endemic equilibrium by choosing one parameter of the model as the bifurcation parameter. Meanwhile, the global asymptotic stabilities of the equilibria are established by constructing suitable Lyapunov functions under some conditions. Furthermore, the authors develop an extended model by incorporating with the intracellular delays and derive global asymptotic stability of the delayed model by constructing Lyapunov functions. Some numerical simulations for justifying the theoretical analysis results are also given. [ABSTRACT FROM AUTHOR]

Caspase-1-mediated pyroptosis is the predominance for driving CD4+ T cells death. Dying infected CD4+ T cells can release inflammatory signals which attract more uninfected CD4+ T cells to die. This paper is devoted to developing a diffusive mathematical model which can make useful contributions to understanding caspase-1-mediated pyroptosis by inflammatory cytokines IL-1β released from infected cells in the within-host environment. The well-posedness of solutions, basic reproduction number, threshold dynamics are investigated for spatially heterogeneous infection. Travelling wave solutions for spatially homogeneous infection are studied. Numerical computations reveal that the spatially heterogeneous infection can make R0>1, that is, it can induce the persistence of virus compared to the spatially homogeneous infection. We also find that the random movements of virus have no effect on basic reproduction number for the spatially homogeneous model, while it may result in less infection risk for the spatially heterogeneous model, under some suitable parameters. Further, the death of infected CD4+ cells which are caused by pyroptosis can make R0<1, that is, it can induce the extinction of virus, regardless of whether or not the parameters are spatially dependent. [ABSTRACT FROM AUTHOR]

The immune system is traditionally classified as a defense system that can discriminate between self and non-self or dangerous and non-dangerous situations, unleashing a tolerogenic reaction or immune response. These activities are mainly coordinated by the interaction between innate and adaptive cells that act together to eliminate harmful stimuli and keep tissue healthy. However, healthy tissue is not always the end point of an immune response. Much evidence has been accumulated over the years, showing that the immune system has complex, diversified, and integrated functions that converge to maintaining tissue homeostasis, even in the absence of aggression, interacting with the tissue cells and allowing the functional maintenance of that tissue. One of the main cells known for their function in helping the immune response through the production of cytokines is CD4+ T lymphocytes. The cytokines produced by the different subtypes act not only on immune cells but also on tissue cells. Considering that tissues have specific mediators in their architecture, it is plausible that the presence and frequency of CD4+ T lymphocytes of specific subtypes (Th1, Th2, Th17, and others) maintain tissue homeostasis. In situations where homeostasis is disrupted, such as infections, allergies, inflammatory processes, and cancer, local CD4+ T lymphocytes respond to this disruption and, as in the healthy tissue, towards the equilibrium of tissue dynamics. CD4+ T lymphocytes can be manipulated by tumor cells to promote tumor development and metastasis, making them a prognostic factor in various types of cancer. Therefore, understanding the function of tissue-specific CD4+ T lymphocytes is essential in developing new strategies for treating tissue-specific diseases, as occurs in cancer. In this context, this article reviews the evidence for this hypothesis regarding the phenotypes and functions of CD4+ T lymphocytes and compares their contribution to maintaining tissue homeostasis in different organs in a steady state and during tumor progression. [ABSTRACT FROM AUTHOR]

In response to an immune challenge, naive T cells undergo a transition from a quiescent to an activated state acquiring the effector function. Concurrently, these T cells reprogram cellular metabolism, which is regulated by iron. We and others have shown that iron homeostasis controls proliferation and mitochondrial function, but the underlying mechanisms are poorly understood. Given that iron derived from heme makes up a large portion of the cellular iron pool, we investigated iron homeostasis in T cells using mice with a T cell-specific deletion of the heme exporter, FLVCR1 [referred to as knockout (KO)]. Our finding revealed that maintaining heme and iron homeostasis is essential to keep naive T cells in a quiescent state. KO naive CD4 T cells exhibited an iron-overloaded phenotype, with increased spontaneous proliferation and hyperactive mitochondria. This was evidenced by reduced IL-7R and IL-15R levels but increased CD5 and Nur77 expression. Upon activation, however, KO CD4 T cells have defects in proliferation, IL-2 production, and mitochondrial functions. Iron-overloaded CD4 T cells failed to induce mitochondrial iron and exhibited more fragmented mitochondria after activation, making them susceptible to ferroptosis. Iron overload also led to inefficient glycolysis and glutaminolysis but heightened activity in the hexosamine biosynthetic pathway. Overall, these findings highlight the essential role of iron in controlling mitochondrial function and cellular metabolism in naive CD4 T cells, critical for maintaining their quiescent state. [ABSTRACT FROM AUTHOR]

Background: The CD4 T lymphocyte count in people living with HIV (PLHIV) is a predictor for the progression of the disease (AIDS), survival and response to antiretroviral treatment (ART). A CD4 T lymphocyte count of less than 200 cells/mm3 is indicative of a greater risk for the onset of opportunistic diseases and death. Defaulting on treatment for tuberculosis (TB) may impact immune recovery in PLHIV who are taking ART. The aim of this study was to investigate an association of the CD4 lymphocyte with TB treatment Trajectory and with death. Methods: A cohort of PLHIV over eighteen years of age and who were taking ART and who had defaulted on pulmonary TB treatment. Latent Class analysis was used to identify different trajectories of CD4 T lymphocyte counts over time. Results: Latent class 1 (High CD4 trajectory) grouped individuals together who were characterized as maintaining a low probability (0 to 29%) of a CD4 count ≤ 200 cells/mm3over time, while latent class 2 (Low CD4 trajectory) grouped individuals together with a high probability (93% to 60%), and latent class 3 (Fluctuating CD4 trajectory), grouped individuals with a fluctuating probability (66% to 0%). The chance of defaulting on treatment earlier (≤ 90 days) was four times higher in latent class 2 (Low CD4 trajectory). Although there was no statistical significance, there was a higher frequency of deaths in this same latent class. Conclusion: Individuals with a high probability of a CD4 count ≤ 200 cells/ mm3 should be monitored in order to avoid treatment default and thereby prevent death. New studies should be conducted with a larger sample size and a longer follow-up time in PLHIV who initiated ART treatment early so as to support clinical decisions for a better understanding of immune behavior. [ABSTRACT FROM AUTHOR]

T cell is vital in the adaptive immune system, which relays on T-cell receptor (TCR) to recognize and defend against infection and tumors. T cells are mainly divided into well-known CD4+ and CD8+ T cells, which can recognize short peptide antigens presented by major histocompatibility complex (MHC) class II and MHC class I respectively in humoral and cell-mediated immunity. Due to the Human Leukocyte Antigen (HLA) diversity and restriction with peptides complexation, TCRs are quite diverse and complicated. To better elucidate the TCR in humans, the present study shows the difference between the TCR repertoire in CD4+ and CD8+ T cells from 30 healthy donors. The result showed count, clonality, diversity, frequency, and VDJ usage in CD4+ and CD8+ TCR-β repertoire is different, but CDR3 length is not. The Common Clone Cluster result showed that CD4+ and CD8+ TCR repertoires are connected separately between the bodies, which is odd considering the HLA diversity. More knowledge about TCR makes more opportunities for immunotherapy. The TCR repertoire is still a myth for discovery. [ABSTRACT FROM AUTHOR]

While CD4+ T cells are a prerequisite for CD8+ T cell-mediated protection against intracellular hepatotropic pathogens, the mechanisms facilitating the transfer of CD4-help to intrahepatic CD8+ T cells are unknown. Here, we developed an experimental system to investigate cognate CD4+ and CD8+ T cell responses to a model-antigen expressed de novo in hepatocytes and reveal that after initial priming, effector CD4+ and CD8+ T cells migrate into portal tracts and peri-central vein regions of the liver where they cluster with type-1 conventional dendritic cells. These dendritic cells are locally licensed by CD4+ T cells and expand the number of CD8+ T cells in situ, resulting in larger effector and memory CD8+ T cell pools. These findings reveal that CD4+ T cells promote intrahepatic immunity by amplifying the CD8+ T cell response via peripheral licensing of hepatic type-1 conventional dendritic cells and identify intrahepatic perivascular compartments specialized in facilitating effector T cell-dendritic cell interactions. Here, English et al. show that after expanding in lymphoid tissues, CD4+ and CD8+ T cells recognising hepatic antigens migrate into specialised vascular liver areas where CD4+ T cells locally license hepatic dendritic cells and further expand CD8+ T cell numbers. [ABSTRACT FROM AUTHOR]

In HIV-infected people, resting CD4+ T cells are the main reservoir of latent virus and the reason for the failure of drug therapy to cure HIV infection. Still, we do not have a complete understanding of the factors regulating HIV replication in these cells. A recent paper in Cell describes a new trick that the virus uses to infect resting T cells. Interaction between the viral gp120 and cellular HIV coreceptor, CXCR4, during viral entry initiates signaling that activates cofilin, the main regulator of actin polymerization. As a result of this activation, actin is depolymerized, thus destroying the natural barrier to HIV replication. I discuss implications of this study for our understanding of HIV biology and development of novel anti-HIV therapeutic approaches. [ABSTRACT FROM AUTHOR]

Background: Investigation of host responses to blood stages of Plasmodium spp, and the immunopathology associated with this phase of the life cycle are often performed on mice infected directly with infected red blood cells. Thus, the effects of mosquito bites and the pre-erythrocytic stages of the parasite, which would be present in natural infection, are ignored In this paper, Plasmodium chabaudi chabaudi infections of mice injected directly with infected red blood cells were compared with those of mice infected by the bites of infected mosquitoes, in order to determine whether the courses of primary infection and splenic CD4 T cell responses are similar. Methods: C57Bl/6 mice were injected with red blood cells infected with P. chabaudi (ER) or infected via the bite of Anopheles stephensi mosquitoes. Parasitaemia were monitored by Giemsastained thin blood films. Total spleen cells, CD4+ T cells, and cytokine production (IFN-γ, IL-2, IL-4, IL-10) were analysed by flow cytometry. In some experiments, mice were subjected to bites of uninfected mosquitoes prior to infectious bites in order to determine whether mosquito bites per se could affect a subsequent P. chabaudi infection. Results: P. chabaudi (ER) infections initiated by mosquito bite were characterized by lower parasitaemia of shorter duration than those observed after direct blood challenge. However, splenomegaly was comparable suggesting that parasitaemia alone does not account for the increase in spleen size. Total numbers of CD4 T cells and those producing IFN-γ, IL-10 and IL-2 were reduced in comparison to direct blood challenge. By contrast, the reduction in IL-4 producing cells was less marked suggesting that there is a proportionally lower Th1-like response in mice infected via infectious mosquitoes. Strikingly, pre-exposure to bites of uninfected mosquitoes reduced the magnitude and duration of the subsequent mosquito-transmitted infection still further, but enhanced the response of CD4 T cells producing IFN-γ and IL-4. Conclusion: The data in this paper suggest that studying early host responses in blood stage malaria infections measured after direct blood challenge of mice may not completely reflect the natural situation, and more detailed investigations of blood-stage immunity after mosquito transmission in experimental models should be considered. [ABSTRACT FROM AUTHOR]

In this paper, we construct an HIV infection model which includes latent infection, logistic growth for healthy CD4 T-cells, and antiretroviral therapy. We obtain the global asymptotic stability of the uninfected equilibrium by constructing a Lyapunov function, and we give a sufficient condition for the local asymptotic stability of the infected equilibrium. We also use the latin hypercube sampling technique to identify the key parameters in determining the stability of the infected equilibrium. By numerical simulations, we observe that the model without logistic growth would underestimate the number of infectious virions, while the model without latent infection would overestimate the number of infectious virions. [ABSTRACT FROM AUTHOR]

Conventional antiviral memory CD4 T cells typically arise during the first two weeks of acute infection. Unlike most viruses, cytomegalovirus (CMV) exhibits an extended persistent replication phase followed by lifelong latency accompanied with some gene expression. We show that during mouse CMV (MCMV) infection, CD4 T cells recognizing an epitope derived from the viral M09 protein only develop after conventional memory T cells have already peaked and contracted. Ablating these CD4 T cells by mutating the M09 genomic epitope in the MCMV Smith strain, or inducing them by introducing the epitope into the K181 strain, resulted in delayed or enhanced control of viral persistence, respectively. These cells were shown to be unique compared to their conventional memory counterparts; producing higher IFNγ and IL-2 and lower IL-10 levels. RNAseq analyses revealed them to express distinct subsets of effector genes as compared to classical CD4 T cells. Additionally, when M09 cells were induced by epitope vaccination they significantly enhanced protection when compared to conventional CD4 T cells alone. These data show that late-rising CD4 T cells are a unique memory subset with excellent protective capacities that display a development program strongly differing from the majority of memory T cells. Author summary: Functional memory T cells are critical to ultimately control chronic viral infection. We show that cytomegalovirus (CMV) induces a population of unique memory CD4 T cells that expand late during infection and resolve viral persistence much better than conventional T memory cells. Mutation of the genomic CMV epitope recognized by these T cells results in markedly enhanced persistent replication, and introduction of the epitope into a CMV strain that lacks it induces much quicker resolution of persistence. When induced via vaccination, we show these T cells provide significantly enhanced protection against acute viral challenge. Together our study identifies a novel population of CD4 T cells that utilize distinct effector function(s) to rapidly resolve persistent viral replication. [ABSTRACT FROM AUTHOR]

After Mycobacterium tuberculosis (Mtb) infection, many effector T cells traffic to the lungs, but few become activated. Here we use an antigen receptor reporter mouse (Nur77-GFP) to identify recently activated CD4 T cells in the lungs. These Nur77-GFPHI cells contain expanded TCR clonotypes, have elevated expression of co-stimulatory genes such as Tnfrsf4/OX40, and are functionally more protective than Nur77-GFPLO cells. By contrast, Nur77-GFPLO cells express markers of terminal exhaustion and cytotoxicity, and the trafficking receptor S1pr5, associated with vascular localization. A short course of immunotherapy targeting OX40+ cells transiently expands CD4 T cell numbers and shifts their phenotype towards parenchymal protective cells. Moreover, OX40 agonist immunotherapy decreases the lung bacterial burden and extends host survival, offering an additive benefit to antibiotics. CD4 T cells from the cerebrospinal fluid of humans with HIV-associated tuberculous meningitis commonly express surface OX40 protein, while CD8 T cells do not. Our data thus propose OX40 as a marker of recently activated CD4 T cells at the infection site and a potential target for immunotherapy in tuberculosis. Marking of recently activated T cells may help further our understanding of immunity against Mycobacterium tuberculosis (Mtb). Here the authors use Nur77-GFP reporter mice infected with Mtb and systems data approaches to implicate OX40 as a marker for recently activated, functionally and transcriptome-wise distinct CD4 T cells, and as a potential target for immunotherapy. [ABSTRACT FROM AUTHOR]

Virologic suppression with antiretroviral therapy (ART) has significantly improved health outcomes for people living with HIV, yet challenges related to chronic inflammation in the central nervous system (CNS)—known as Neuro-HIV- persist. As primary targets for HIV-1 with the ability to survey and populate the CNS and interact with myeloid cells to co-ordinate neuroinflammation, CD4 T cells are pivotal in Neuro-HIV. Despite their importance, our understanding of CD4 T cell distribution in virus-targeted CNS tissues, their response to infection, and potential recovery following initiation of ART remain limited. To address these gaps, we studied ten SIVmac251-infected rhesus macaques using an ART regimen simulating suboptimal adherence. We evaluated four macaques during the acute phase pre-ART and six during the chronic phase. Our data revealed that HIV target CCR5+ CD4 T cells inhabit both the brain parenchyma and adjacent CNS tissues, encompassing choroid plexus stroma, dura mater, and the skull bone marrow. Aligning with the known susceptibility of CCR5+ CD4 T cells to viral infection and their presence within the CNS, high levels of viral RNA were detected in the brain parenchyma and its border tissues during acute SIV infection. Single-cell RNA sequencing of CD45+ cells from the brain revealed colocalization of viral transcripts within CD4 clusters and significant activation of antiviral molecules and specific effector programs within T cells, indicating CNS CD4 T cell engagement during infection. Acute infection led to marked imbalance in the CNS CD4/CD8 ratio which persisted into the chronic phase. These observations underscore the functional involvement of CD4 T cells within the CNS during SIV infection, enhancing our understanding of their role in establishing CNS viral presence. Our findings offer insights for potential T cell-focused interventions while underscoring the challenges in eradicating HIV from the CNS, particularly in the context of sub-optimal ART. Author summary: Antiretroviral therapy (ART) has improved health outcomes of people living with HIV. However, there are still challenges, especially in the central nervous system (CNS), where ongoing inflammation can lead to neurological disorders. Our study focused on understanding the role of CD4 T cells in the brain during HIV infection and sub-optimal treatment adherence. We used a model with SIV-infected rhesus monkeys to study the AIDS virus in the brain and surrounding tissues. We discovered that a subset of CD4 T cells, which are vulnerable to HIV, are present throughout the CNS. During the early stages of infection, we noticed high levels of the virus in both the brain and nearby tissues. By examining these CD4 T cells at a single-cell level, we found that they actively respond to the virus by initiating specific antiviral effector functions to fight it. Overall, our study helps us understand the role of CD4 T cells within the CNS during both acute and chronic HIV infection. This knowledge could help us develop new ways to target the virus in the CNS and devise treatments for complications related to Neuro-HIV. [ABSTRACT FROM AUTHOR]

Having a large number of sufficiently abundant T cell clones is important for adequate protection against diseases. However, as shown in this paper and elsewhere, between young adulthood and >70 y of age the effective clonal diversity of naive CD4/CD8 T cells found in human blood declines by a factor of >10. (Effective clonal diversity accounts for both the number and the abundance of T cell clones.) The causes of this observation are incompletely understood. A previous study proposed that it might result from the emergence of certain rare, replication-enhancing mutations in T cells. In this paper, we propose an even simpler explanation: that it results from the loss of T cells that have attained replicative senescence (i.e., the Hayflick limit). Stochastic numerical simulations of naive T cell population dynamics, based on experimental parameters, show that the rate of homeostatic T cell proliferation increases after the age of ~60 y because naive T cells collectively approach replicative senescence. This leads to a sharp decline of effective clonal diversity after ~70 y, in agreement with empirical data. A mathematical analysis predicts that, without an increase in the naive T cell proliferation rate, this decline will occur >50 yr later than empirically observed. These results are consistent with a model in which exhaustion of the proliferative capacity of naive T cells causes a sharp decline of their effective clonal diversity and imply that therapeutic potentiation of thymopoiesis might either prevent or reverse this outcome. [ABSTRACT FROM AUTHOR]

The progressive loss of CD4+ T cell population is the hallmark of HIV-1 infection but the mechanism underlying the slow T cell decline remains unclear. Some recent studies suggested that pyroptosis, a form of programmed cell death triggered during abortive HIV infection, is associated with the release of inflammatory cytokines, which can attract more CD4+ T cells to be infected. In this paper, we developed mathematical models to study whether this mechanism can explain the time scale of CD4+ T cell decline during HIV infection. Simulations of the models showed that cytokine induced T cell movement can explain the very slow decline of CD4+ T cells within untreated patients. The long-term CD4+ T cell dynamics predicted by the models were shown to be consistent with available data from patients in Rio de Janeiro, Brazil. Highly active antiretroviral therapy has the potential to restore the CD4+ T cell population but CD4+ response depends on the effectiveness of the therapy, when the therapy is initiated, and whether there are drug sanctuary sites. The model also showed that chronic inflammation induced by pyroptosis may facilitate persistence of the HIV latent reservoir by promoting homeostatic proliferation of memory CD4+ cells. These results improve our understanding of the long-term T cell dynamics in HIV-1 infection, and support that new treatment strategies, such as the use of caspase-1 inhibitors that inhibit pyroptosis, may maintain the CD4+ T cell population and reduce the latent reservoir size. [ABSTRACT FROM AUTHOR]

The study of the initial phase of the adaptive immune response after first antigen encounter provides essential information on the magnitude and quality of the immune response. This phase is characterized by proliferation and dissemination of T cells in the lymphoid organs. Modeling and identifying the key features of this phenomenon may provide a useful tool for the analysis and prediction of the effects of immunization. This knowledge can be effectively exploited in vaccinology, where it is of interest to evaluate and compare the responses to different vaccine formulations. The objective of this paper is to construct a stochastic model based on branching process theory, for the dissemination network of antigen-specific CD4+ T cells. The devised model is validated on in vivo animal experimental data. The model presented has been applied to the vaccine immunization context making references to simple proliferation laws that take into account division, death and quiescence, but it can also be applied to any context where it is of interest to study the dynamic evolution of a population. [ABSTRACT FROM AUTHOR]

This paper proposes an optimal control problem, with the final goal of implementing an optimal treatment protocol which could maximize the uninfected CD4+T cells and minimize the cost of drug, utilizing a system of ordinary differential equations which describes the interaction of the immune system with the human immunodeficiency virus(HIV). The optimal pair of control and trajectories of this nonlinear system with quadratic cost functional is obtained by Fourier series approximation. The method is based upon expanding time varying functions in the nonlinear system as their Fourier series, using the operational matrices for integration and product. The problem is reduced into a set of algebraic equations. [ABSTRACT FROM AUTHOR]

Aim and Objective: HIV (Human Immunodeficiency Virus) has been reported to weaken the immune system by binding to CD4+ receptor of T lymphocytes, thereby making the affected individual to become more susceptible to several microbial infections leading to life threatening problems. Recent literature indicate there is promsing advancement in identifying drug targets through CD4+ receptor binding capabilities with its ligand. The main purpose of this paper was to study the various molecular interactions of HIV to other molecules like receptors CD4+ and also co-receptors like CCR5 and CXCR4. Materials and Required: The molecules are going to be modeled by using software known as Swiss PDB viewer. The first objective is to get the FASTA sequence from the NCBI website. Then we need to paste the sequence onto the Swiss PDB viewer. Conclusion: The requierd protein/molecule is modeled. We are going to follow this method to obtain templates and modles for the following molecukles: HIV, GP120, CCR5 and CXCR4. [ABSTRACT FROM AUTHOR]

Single-cell gene expression analysis using sequencing (scRNA-seq) has gained increased attention in the past decades for studying cellular transcriptional programs and their heterogeneity in an unbiased manner, and novel protocols allow the simultaneous measurement of gene expression, T-cell receptor clonality and cell surface protein expression. In this article, we describe the methods to isolate scRNA/TCR-seq-compatible CD4+ T cells from murine tissues, such as skin, spleen, and lymph nodes. We describe the processing of cells and quality control parameters during library preparation, protocols for multiplexing of samples, and strategies for sequencing. Moreover, we describe a step-by-step bioinformatic analysis pipeline from sequencing data generated using these protocols. This includes quality control, preprocessing of sequencing data and demultiplexing of individual samples. We perform quantification of gene expression and extraction of T-cell receptor alpha and beta chain sequences, followed by quality control and doublet detection, and methods for harmonization and integration of datasets. Next, we describe the identification of highly variable genes and dimensionality reduction, clustering and pseudotemporal ordering of data, and we demonstrate how to visualize the results with interactive and reproducible dashboards. We will combine different analytic R-based frameworks such as Bioconductor and Seurat, illustrating how these can be interoperable to optimally analyze scRNA/TCR-seq data of CD4+ T cells from murine tissues. [ABSTRACT FROM AUTHOR]

α2,6‐sialylation, catalyzed by α2,6‐sialyltransferase (ST6GAL1), plays a pivotal role in immune responses. However, the role of ST6GAL1 in the pathogenesis of ulcerative colitis (UC) remains unknown. ST6GAL1 mRNA is highly expressed in UC tissues compared with the corresponding adjacent normal tissues, and α2,6‐sialylation is significantly increased in the colon tissues of patients with UC. The expression of ST6GAL1 and proinflammatory cytokines, such as interleukin (IL)‐2, IL‐6, IL‐17, and interferon‐gamma, is also increased. The number of CD4+ T cells increases in UC patients. St6gal1 gene knockout (St6gal1−/‐) rats are established by clustered regularly interspaced short palindromic repeats (CRISPR)‐associated gene knockout system. St6gal1 deficiency reduces the levels of pro‐inflammatory cytokines and alleviates colitis symptoms in UC model rats. Ablation of α2,6‐sialylation inhibits the transport of the TCR to lipid rafts and suppresses CD4+ T‐cell activation. The attenuation of TCR signaling downregulates the expression of NF‐κB in ST6GAL1‐/‐ CD4+ T‐cells. Moreover, NF‐κB could bind to the ST6GAL1 promoter to increase its transcription. Ablation of ST6GAL1 downregulates the expression of NF‐κB and reduces the production of proinflammatory cytokines to relieve UC pathogenesis, which is a potential novel target for the clinical treatment of UC. [ABSTRACT FROM AUTHOR]

Detailed characterisation of immune responses induced by COVID-19 vaccines rolled out in India: COVISHIELDTM (CS) and COVAXIN® (CO) in a pre-exposed population is only recently being discovered. We addressed this issue in subjects who received their primary series of vaccination between November 2021 and January 2022. Both vaccines are capable of strongly boosting Wuhan Spike-specific neutralising antibody, polyfunctional Th1 cytokine producing CD4+ T-cells and single IFN-γ + CD8+ T-cells. Consistent with inherent differences in vaccine platform, the vector-based CS vaccine-induced immunity was of greater magnitude, breadth, targeting Delta and Omicron variants compared to the whole-virion inactivated vaccine CO, with CS vaccinees showing persistent CD8+ T-cells responses until 3 months post primary vaccination. This study provides detailed evidence on the magnitude and quality of CS and CO vaccine induced responses in subjects with pre-existing SARS-CoV-2 immunity in India, thereby mitigating vaccine hesitancy arguments in such a population, which remains a global health challenge. [ABSTRACT FROM AUTHOR]

Following viral clearance, antigen-specific CD4+ T cells contract and form a pool of distinct Th1 and Tfh memory cells that possess unique epigenetic programs, allowing them to rapidly recall their specific effector functions upon rechallenge. DNA methylation programing mediated by the methylcytosine dioxygenase Tet2 contributes to balancing Th1 and Tfh cell differentiation during acute viral infection; however, the role of Tet2 in CD4+ T cell memory formation and recall is unclear. Using adoptive transfer models of antigen-specific wild type and Tet2 knockout CD4+ T cells, we find that Tet2 is required for full commitment of CD4+ T cells to the Th1 lineage and that in the absence of Tet2, memory cells preferentially recall a Tfh like phenotype with enhanced expansion upon secondary challenge. These findings demonstrate an important role for Tet2 in enforcing lineage commitment and programing proliferation potential, and highlight the potential of targeting epigenetic programing to enhance adaptive immune responses. [ABSTRACT FROM AUTHOR]

CD4+ T cells have been found to play critical roles in the control of both acute and chronic Toxoplasma infection. Previous studies identified a protective role for the Toxoplasma CD4+ T cell-eliciting peptide AS15 (AVEIHRPVPGTAPPS) in C57BL/6J mice. Herein, we found that immunizing mice with AS15 combined with GLA-SE, a TLR-4 agonist in emulsion adjuvant, can be either helpful in protecting male and female mice at early stages against Type I and Type II Toxoplasma parasites or harmful (lethal with intestinal, hepatic, and spleen pathology associated with a storm of IL6). Introducing the universal CD4+ T cell epitope PADRE abrogates the harmful phenotype of AS15. Our findings demonstrate quantitative and qualitative features of an effective Toxoplasma-specific CD4+ T cell response that should be considered in testing next-generation vaccines against toxoplasmosis. Our results also are cautionary that individual vaccine constituents can cause severe harm depending on the company they keep. [ABSTRACT FROM AUTHOR]

Background: Protein arginine methyltransferase 5 (Prmt5) is the main type II methyltransferase, catalyzes protein arginine residue symmetric dimethylation, and modulates normal cellular physiology and disease progression. Prmt5 inhibition or deletion in CD4+ T cells has been reported to ameliorate experimental autoimmune encephalomyelitis (EAE), but the detailed molecular mechanisms have not yet been elucidated. Methods: EAE was induced by administration of myelin oligodendrocyte glycoprotein (MOG35–55) in T cells Prmt5 conditional knockout (CD4-cre-Prmt5fl/fl, Prmt5cko) and Prmt5fl/fl (WT) mice. Flow cytometry, single-cell RNA sequencing, ATAC sequencing and chromatin immunoprecipitation assay (ChIP) approaches were used to explore the detail mechanisms. Results: We find that Prmt5cko mice are resistant to EAE; infiltrating inflammatory CD4+ T cells in the central nervous system (CNS) are greatly reduced. However, in Prmt5cko mice, T cells in the spleen show much more proliferation and activation properties, the total number of CD4+ T cells in the spleen is not reduced, and the percentage of Rora+ CD4+ T cells is elevated. Also, CD4+ T cells express lower levels of S1pr1 and Klf2 than WT mice, which may influence pathogenic CD4+ T-cell egress from the spleen and migration to the CNS. Moreover, the single-cell ATAC sequence and ChIP assay reveal that the transcription factor Klf2 is enriched at the S1pr1 promoter and that Klf2 motif activity is reduced in Prmt5cko mice. Conclusions: Our study delineates the undiscovered role of Prmt5 in T-cell biology in which Prmt5 may inhibit Klf2-S1pr1 pathway to ameliorate EAE disease. Controlling T-cell Prmt5 expression may be helpful for the treatment of autoimmune diseases. [ABSTRACT FROM AUTHOR]

A systemic and local inflammatory immune imbalance is thought to be the cause of traumatic tracheal stenosis (TS). However, with CD4+ T lymphocytes being the predominant immune cells in TS, the mechanism of action and recruitment has not been described. In our research, using flow cytometry, ELISA, immunofluorescence, and Transwell chamber assays, the expression, distribution, and potential chemotactic function of CD4+ T cells in TS patients were examined before and after treatment. The results showed that the untreated group had significantly more CD4+ T cells and their secreted TGF‐β1 than the treated group. Additionally, the untreated group's CD4+ T cells showed a significant rise in CCL22 and CCL1, as well as a larger proportion of CCR4 and CCR8. CD4+ T cells and CD68+ macrophages located in TS also expressed CCL1 and CCL22. In vitro, anti‐CCL1 and anti‐CCL22 can partially block the chemoattractant effect of TS bronchoalveolar lavage (BAL) on purified CD4+ T cells. The findings of this study indicated that TS contained unbalanced CD4 immune cells that were actively recruited locally by CCR4/CCL22 and CCR8/CCL1. As a result, it is anticipated that CD4 immune rebalancing can serve as a novel treatment for TS. [ABSTRACT FROM AUTHOR]

This paper presents the design, fabrication, and testing of a magnetophoretic bioseparation chip for the rapid isolation and concentration of CD4 + T cells from the peripheral blood. In a departure from conventional magnetic separation techniques, this microfluidic-based bioseperation device has several unique features, including locally engineered magnetic field gradients and a continuous flow with a buffer switching scheme to improve the performance of the separation process. Additionally, the chip is capable of processing significantly smaller sample volumes than conventional methods and sample losses are eliminated due to decreased handling. Furthermore, the possibility of sample-to-sample contamination is reduced with the disposable format. The overall dimensions of the device were 22 mm by 60 mm by 1 mm, approximately the size of a standard microscope slide. The results indicate a cell purity of greater than 95% at a sample flow rate of 50 ml/h and a cell recovery of 81% at a sample flow rate of 10 ml/h. The cell purity was found to increase with increasing the sample flow rate. However, the cell recovery decreases with an increase in the flow rate. A parametric study was also performed to investigate the effects of channel height, substrate thickness, magnetic bead size, and number of beads per cell on the cell separation performance. [ABSTRACT FROM AUTHOR]

Natural killer ( NK) cells provide an immediate first line of defence against viral infections. Memory responses, maintained by CD4+ T cells, require exposure to viral antigen and provide long-term protection against future infections. It is known that NK cells can promote the development of the adaptive response through cytokine production and cross-talk with antigen-presenting cells. In this paper however, we summarize a series of recent publications, in mouse models and for the first time in man, with the unifying message that rapid viral antigen control by the innate immune system limits antigen exposure to CD4+ cells thereby abrogating the development of a memory response. We discuss the significant implication of these studies on viral treatment strategies and immunization models. [ABSTRACT FROM AUTHOR]

While antiretroviral drugs can drive HIV to undetectably low levels in the blood, eradication is hindered by the persistence of long-lived, latently infected memory CD4 T cells. Immune activation therapy aims to eliminate this latent reservoir by reactivating these memory cells, exposing them to removal by the immune system and the cytotoxic effects of active infection. In this paper, we develop a mathematical model that investigates the use of immune activation strategies while limiting virus and latent class rebound. Our model considers infection of two memory classes, central and transitional CD4 T cells and the role that general immune activation therapy has on their elimination. Further, we incorporate ways to control viral rebound by blocking activated cell proliferation through anti proliferation therapy. Using the model, we provide insight into the control of latent infection and subsequently into the long term control of HIV infection. [ABSTRACT FROM AUTHOR]

CD4+T cells are crucial in achieving a regulated effective immune response to pathogens. Naive CD4+T cells are activated after interaction with antigen-MHC complex and differentiate into specific subtypes depending mainly on the cytokine milieu of the microenvironment. Besides the classical T-helper 1 and T-helper 2, other subsets have been identified, including T-helper 17, regulatory T cell, follicular helper T cell, and T-helper 9, each with a characteristic cytokine profile. For a particular phenotype to be differentiated, a set of cytokine signaling pathways coupled with activation of lineage-specific transcription factors and epigenetic modifications at appropriate genes are required. The effector functions of these cells are mediated by the cytokines secreted by the differentiated cells. This paper will focus on the cytokine-signaling and the network of transcription factors responsible for the differentiation of naive CD4+T cells [ABSTRACT FROM AUTHOR]

Despite variability, the majority of HIV-1-infected individuals progress to AIDS characterized by high viral load andmassive CD4+ T-cell depletion. However, there is a subset of HIV-1-positive individuals that does not progress and spontaneously maintains an undetectable viral load. This infrequent patient population is defined as HIV-1 controllers (HIV controllers), and represents less than 1% of HIV-1-infected patients. HIV-1-specific CD4+ T cells and the pool of central memory CD4+ T cells are also preserved despite immune activation due to HIV-1 infection. The majority of HIV controllers are also defined by the absence of massive CD4+ T-cell depletion, even after 10 years of infection. However, the mechanisms involved in protection against HIV-1 disease progression have not been elucidated yet. Controllers represent a heterogeneous population; we describe in this paper some common characteristics concerning innate immune response and CD4+ T cells of HIV controllers. [ABSTRACT FROM AUTHOR]

Mucosal-associated invariant T (MAIT) cells are characterized by a semi-invariant TCR that recognizes vitamin B metabolite Ags presented by the MHC-related molecule MR1. Their Ag restriction determines a unique developmental lineage, imbuing a tissue-homing, preprimed phenotype with antimicrobial function. A growing body of literature indicates that MR1-restricted T cells are more diverse than the MAIT term implies. Namely, it is increasingly clear that TCR a- and TCR b-chain diversity within the MR1-restricted repertoire provides a potential mechanism of Ag discrimination, and context-dependent functional variation suggests a role for MR1-restricted T cells in diverse physiological settings. In this paper, we summarize MR1-restricted T cell biology, with an emphasis on TCR diversity, Ag discrimination, and functional heterogeneity. [ABSTRACT FROM AUTHOR]

CD4 T cells play a central role in the immune response to malaria. They are required to help B cells produce the antibody that is essential for parasite clearance. They also produce cytokines that amplify the phagocytic and parasitocidal response of the innate immune system, as well as dampening this response later on to limit immunopathology. Therefore, understanding the mechanisms by which T helper cells are activated and the requirements for development of specific, and effective, T cell memory and immunity is essential in the quest for a malaria vaccine. In this paper on the CD4 session of the Immunology of Malaria Infections meeting, we summarize discussions of CD4 cell priming and memory in malaria and in vaccination and outline critical future lines of investigation. B. Stockinger and M.K. Jenkins proposed cutting edge experimental systems to study basic T cell biology in malaria. Critical parameters in T cell activation include the cell types involved, the route of infection and the timing and location and cell types involved in antigen presentation. A new generation of vaccines that induce CD4 T cell activation and memory are being developed with new adjuvants. Studies of T cell memory focus on differentiation and factors involved in maintenance of antigen specific T cells and control of the size of that population. To improve detection of T cell memory in the field, efforts will have to be made to distinguish antigen-specific responses from cytokine driven responses. [ABSTRACT FROM AUTHOR]

The requirements for the eradication of HIV in infected individuals are unknown. Intermittent administration of the immune activator interleukin-2 (IL-2) in combination with highly-active anti-retroviral therapy (HAART) has been suggested as an effective strategy to realize long-term control of HIV replication in vivo . However, potential latent virus reservoirs are considered to be a major impediment in achieving this goal. In this paper, a new mathematical model is designed and used to monitor the interactions between HIV, CD4+ T-cells, CD8+ T-cells, productively infected and latently infected CD4+ T-cells, and to evaluate therapeutic strategies during the first 3 years of HIV infection. The model shows that current anti-HIV therapies, including intermittent IL-2 and HAART, are insufficient in achieving eradication of HIV. However, it suggests that the HIV eradication may indeed be theoretically feasible if such therapy is administered continuously (without interruption) under some specified conditions. These conditions may realistically be achieved using an agent (such as a putative anti-HIV vaccine) that brings about a concomitant increase in the proliferation of HIV-specific CD4+ T- and CD8+ T-cells and the differentiation of CD8+ T-cells into anti-HIV cytotoxic T lymphocytes (CTLs). [ABSTRACT FROM AUTHOR]

Introduction: Sjögren's syndrome (SS) is a chronic autoimmune disorder characterized by exocrine gland dysfunction, leading to loss of salivary function. Histological analysis of salivary glands from SS patients reveals a high infiltration of immune cells, particularly activated CD4+ T cells. Thus, interventions targeting abnormal activation of CD4+ T cells may provide promising therapeutic strategies for SS. Here, we demonstrate that Hect, uba, and wwe domain containing 1 (HUWE1), a member of the eukaryotic Hect E3 ubiquitin ligase family, plays a critical role in CD4+ T-cell activation and SS pathophysiology. Methods: In the context of HUWE1 inhibition, we investigated the impact of the HUWE1 inhibitor BI8626 and sh-Huwe1 on CD4+ T cells in mice, focusing on the assessment of activation levels, proliferation capacity, and cholesterol abundance. Furthermore, we examined the therapeutic potential of BI8626 in NOD/ShiLtj mice and evaluated its efficacy as a treatment strategy. Results: Inhibition of HUWE1 reduces ABCA1 ubiquitination and promotes cholesterol efflux, decreasing intracellular cholesterol and reducing the expression of phosphorylated ZAP-70, CD25, and other activation markers, culminating in the suppressed proliferation of CD4+ T cells. Moreover, pharmacological inhibition of HUWE1 significantly reduces CD4+ T-cell infiltration in the submandibular glands and improves salivary flow rate in NOD/ShiLtj mice. Conclusion: These findings suggest that HUWE1 may regulate CD4+ T-cell activation and SS development by modulating ABCA1-mediated cholesterol efflux and presents a promising target for SS treatment. [ABSTRACT FROM AUTHOR]

Nucleus accumbens‐associated protein 1 (NAC1), a transcriptional cofactor, has been found to play important roles in regulating regulatory T cells, CD8+ T cells, and antitumor immunity, but little is known about its effects on T‐cell memory. In this study, we found that NAC1 expression restricts memory formation of CD4+ T cells during viral infection. Analysis of CD4+ T cells from wild‐type (WT) and NAC1‐deficient (−/−) mice showed that NAC1 is essential for T‐cell metabolism, including glycolysis and oxidative phosphorylation, and supports CD4+ T‐cell survival in vitro. We further demonstrated that a deficiency of NAC1 downregulates glycolysis and correlates with the AMPK‐mTOR pathway and causes autophagy defective in CD4+ T cells. Loss of NAC1 reduced the expression of ROCK1 and the phosphorylation and stabilization of BECLIN1. However, a forced expression of ROCK1 in NAC1−/− CD4+ T cells restored autophagy and the activity of the AMPK‐mTOR pathway. In animal experiments, adoptively transferred NAC1−/− CD4+ T cells or NAC1−/− mice challenged with VACV showed enhanced formation of VACV‐specific CD4+ memory T cells compared to adoptively transferred WT CD4+ T cells or WT mice. This memory T‐cell formation enhancement was abrogated by forcing expression of ROCK1. Our study reveals a novel role for NAC1 as a suppressor of CD4+ T‐cell memory formation and suggests that targeting NAC1 could be a new approach to promoting memory CD4+ T‐cell development, which is critical for an effective immune response against pathogens. [ABSTRACT FROM AUTHOR]

Introduction: Human immunodeficiency virus type 1 (HIV-1) causes a chronic, incurable infection leading to immune activation and chronic inflammation in people with HIV-1 (PWH), even with virologic suppression on antiretroviral therapy (ART). The role of lymphoid structures as reservoirs for viral latency and immune activation has been implicated in chronic inflammation mechanisms. Still, the specific transcriptomic changes induced by HIV-1 infection in different cell types within lymphoid tissue remain unexplored. Methods: In this study, we utilized human tonsil explants from healthy human donors and infected them with HIV-1 ex vivo. We performed single-cell RNA sequencing (scRNA-seq) to analyze the cell types represented in the tissue and to investigate the impact of infection on gene expression profiles and inflammatory signaling pathways. Results: Our analysis revealed that infected CD4+ T cells exhibited upregulation of genes associated with oxidative phosphorylation. Furthermore, macrophages exposed to the virus but uninfected showed increased expression of genes associated with the NLRP3 inflammasome pathway. Discussion: These findings provide valuable insights into the specific transcriptomic changes induced by HIV-1 infection in different cell types within lymphoid tissue. The activation of oxidative phosphorylation in infected CD4+ T cells and the proinflammatory response in macrophages may contribute to the chronic inflammation observed in PWH despite ART. Understanding these mechanisms is crucial for developing targeted therapeutic strategies to eradicate HIV-1 infection in PWH. [ABSTRACT FROM AUTHOR]

Background: With suppressive antiretroviral therapy, HIV infection is well-managed in most patients. However, eradication and cure are still beyond reach due to latent viral reservoirs in CD4 + T cells, particularly in lymphoid tissue environments including the gut associated lymphatic tissues. In HIV patients, there is extensive depletion of T helper cells, particularly T helper 17 cells from the intestinal mucosal area, and the gut is one of the largest viral reservoir sites. Endothelial cells line lymphatic and blood vessels and were found to promote HIV infection and latency in previous studies. In this study, we examined endothelial cells specific to the gut mucosal area—intestinal endothelial cells—for their impact on HIV infection and latency in T helper cells. Results: We found that intestinal endothelial cells dramatically increased productive and latent HIV infection in resting CD4 + T helper cells. In activated CD4 + T cells, endothelial cells enabled the formation of latent infection in addition to the increase of productive infection. Endothelial-cell-mediated HIV infection was more prominent in memory T cells than naïve T cells, and it involved the cytokine IL-6 but did not involve the co-stimulatory molecule CD2. The CCR6 + T helper 17 subpopulation was particularly susceptible to such endothelial-cell-promoted infection. Conclusion: Endothelial cells, which are widely present in lymphoid tissues including the intestinal mucosal area and interact regularly with T cells physiologically, significantly increase HIV infection and latent reservoir formation in CD4 + T cells, particularly in CCR6 + T helper 17 cells. Our study highlighted the importance of endothelial cells and the lymphoid tissue environment in HIV pathology and persistence. [ABSTRACT FROM AUTHOR]

Programmed cell death protein 1 (PD-1), expressed on tumor-infiltrating T cells, is a T cell exhaustion marker. The mechanisms underlying PD-1 upregulation in CD4 T cells remain unknown. Here we develop nutrient-deprived media and a conditional knockout female mouse model to study the mechanism underlying PD-1 upregulation. Reduced methionine increases PD-1 expression on CD4 T cells. The genetic ablation of SLC43A2 in cancer cells restores methionine metabolism in CD4 T cells, increasing the intracellular levels of S-adenosylmethionine and yielding H3K79me2. Reduced H3K79me2 due to methionine deprivation downregulates AMPK, upregulates PD-1 expression and impairs antitumor immunity in CD4 T cells. Methionine supplementation restores H3K79 methylation and AMPK expression, lowering PD-1 levels. AMPK-deficient CD4 T cells exhibit increased endoplasmic reticulum stress and Xbp1s transcript levels. Our results demonstrate that AMPK is a methionine-dependent regulator of the epigenetic control of PD-1 expression in CD4 T cells, a metabolic checkpoint for CD4 T cell exhaustion. The deprivation of amino acids in the tumor microenvironment affects T cell survival and activation. Here the authors show that reduced levels of methionine are associated with PD1 upregulation in CD4+ T cells and that methionine supplementation promotes CD4+ T cell dependent anti-tumor immune responses. [ABSTRACT FROM AUTHOR]

An abstract of the article "Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity" by P. S. Adusumilli and colleagues is presented.