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Homeostasis of lymphocyte numbers is believed to be due to competition between cellular populations for a common niche of restricted size, defined by the combination of interactions and trophic factors required for cell survival. Here we propose a new mechanism: homeostasis of lymphocyte numbers could also be achieved by the ability of lymphocytes to perceive the density of their own populations. Such a mechanism would be reminiscent of the primordial quorum-sensing systems used by bacteria, in which some bacteria sense the accumulation of bacterial metabolites secreted by other elements of the population, allowing them to "count" the number of cells present and adapt their growth accordingly. We propose that homeostasis of CD4+ T cell numbers may occur via a quorum-sensing-like mechanism, where IL-2 is produced by activated CD4+ T cells and sensed by a population of CD4+ Treg cells that expresses the high-affinity IL-2Rα-chain and can regulate the number of activated IL-2-producing CD4+ T cells and the total CD4+ T cell population. In other words, CD4+ T cell populations can restrain their growth by monitoring the number of activated cells, thus preventing uncontrolled lymphocyte proliferation during immune responses. We hypothesize that malfunction of this quorum-sensing mechanism may lead to uncontrolled T cell activation and autoimmunity. Finally, we present a mathematical model that describes the key role of IL-2 and quorum-sensing mechanisms in CD4+ T cell homeostasis during an immune response. [ABSTRACT FROM AUTHOR]

Cooperation between the innate and adaptive immune responses is critical for enabling protective immunity against various invading microbes. Distinct types of effector T cells have different functions in adaptive immune responses. Th1 cells play important roles in the control of intracellular bacteria by producing IFN-γ to activate macrophages and in anti-viral immunity by producing IFN-γ and activating cytotoxic T lymphocytes. Th2 cell-derived cytokines are important in activating mast cells, eosinophils, and goblet cells in anti-helminth immunity. Th17 cells are pivotal for the inflammatory response mediated by neutrophils, which resists extracellular bacterial infection. In all cases, it is critical that the innate immune responses limit the growth and expansion of invading microbes until antigen-specific adaptive immune responses are established. Recent studies have identified multiple subsets in innate lymphocytes corresponding to previously defined Th subsets. Classical natural killer cells, RORγ+ lymphoid tissue inducer-related cells, and Th2-type innate lymphocytes play distinct roles in innate immune responses by producing Th1, Th17, and Th2 cytokines, respectively. Cooperation between innate lymphocytes and antigen-specific T and B cells are likely important in protective immunity against distinct types of microbes. The most recently identified subset is the RORγ-independent Lin-Thy-1+IL-7R+GATA3+ innate lymphocyte subset such as natural helper (NH) cell, which is Id2- and IL-7-dependent. This population produces Th2 cytokines, most notably IL-5 and IL-13, and plays a major role in innate immune responses during anti-helminth immunity. In addition, these cells are likely involved in the pathophysiology of some types of allergic diseases. We summarize here current knowledge regarding various innate lymphocyte subsets. In particular, we focus on the Th2-type innate lymphocyte subset. [ABSTRACT FROM AUTHOR]

Summary Clinical trials have pointed out the promising role of co-stimulation blocker Belatacept for improvement of graft function and avoidance of undesired side-effects associated with calcineurin-inhibitors (CNI). However, due to the worldwide limited availability of appropriate patients, almost no data exist to assess the effects of sustained application of this immunomodulator on the recipient's immune system. The aim of this study was to reveal specific alterations in the composition of immunologic subpopulations potentially involved in development of tolerance or chronic graft rejection following long-term Belatacept therapy. For this, peripheral lymphocyte subsets of kidney recipients treated with Belatacept ( n = 5; average 7.8 years) were determined by flow-cytometry and compared with cells from matched patients on CNI ( n = 9) and healthy controls ( n = 10). T cells capable of producing IL-17 and serum levels of soluble CD30 were quantified. Patients on CNI showed a higher frequency of CD4+CD161+ Th17-precursors and IL-17-producing CD4+ T cells than Belatacept patients and controls. Significantly higher serum levels of soluble CD30 were observed in CNI patients, indicating a possible involvement of the CD30/CD30L-system in Th17-differentiation. No differences were found concerning CD4+CD25+CD127lowFoxP3+ regulatory T cells. In conclusion, patients on therapy with Belatacept did not show a comparable Th17-profile to that seen in individuals with chronic intake of CNI. The distinct effects of Belatacept on Th17-immunity might prove beneficial for the long-term outcome following kidney transplantation. [ABSTRACT FROM AUTHOR]

Summary Laboratory mice are born lymphopenic and demonstrate lymphopenia-induced proliferation that generates memory T cells, yet they are prone to immunologic tolerance. Here we tested whether these fundamental immunologic observations apply to higher animals by studying the immune system of infant baboons. Using flow cytometry of the peripheral blood cells, it was found that baboons are born relatively lymphopenic and subsequently expand their initially naïve T cell pool with increasing numbers of memory T cells. After transplantation of an artery patch allograft or xenograft, non-immunosuppressed recipients readily mounted an immune response against donor-type antigens, as evidenced by mixed lymphocyte reaction. Immunosuppression with anti-thymocyte globulin (ATG), anti-CD154 mAb, and mycophenolate mofetil prevented T cell-mediated rejection. After lymphocyte depletion with ATG, homeostatic T cell proliferation was observed. In conclusion, the baboon proved a suitable model to investigate the infant immune system. In this study, neonatal lymphopenia and expansion of the memory T cell population were observed but, unlike mice, there were no indications that infant baboons are prone to T cell tolerance. The expansion of memory T cells during the neonatal period or after induction therapy may actually form an obstacle to tapering immunosuppressive therapy, or ultimately achieving immunologic tolerance. [ABSTRACT FROM AUTHOR]

Apoptosis controls the adaptive immune system through regulation of central and peripheral lymphocyte deletion. Therefore, substances that selectively interact with the intrinsic apoptosis pathway in lymphocytes offer unexplored opportunities to pharmacologically modulate the immune response. Here, we present evidence that the BH3-mimetic ABT-737 suppresses allogeneic immune responses. In vitro, ABT-737 prevented allogeneic T-cell activation, proliferation, and cytotoxicity by apoptosis induction, but without impairing the physiological functions of remaining viable T cells. In vivo, ABT-737 was highly selective for lymphoid cells and inhibited allogeneic T- and B-cell responses after skin transplantation. The immunosuppressive effect of ABT-737 was markedly increased in combination with low-dose cyclosporine A, as shown by the induction of long-term skin graft survival without significant inflammatory infiltrates in 50% of the recipients in an MHC class I single antigen mismatched model. Thus, pharmacological targeting of Bcl-2 proteins represents a novel immunosuppressive approach to prevent rejection of solid organ allografts. [ABSTRACT FROM AUTHOR]

Diltiazem is a calcium channel antagonist that has been commonly associated with currently used immunosuppressants to prevent acute graft rejection in humans. In this study, we examined the possibility that diltiazem may affect human dendritic cell (DC) functions in response to lipopolysaccharide (LPS) stimulation and may induce the generation of DC with the capacity to generate CD4 regulatory T cells (Tregs). Blood monocytes were cultured in the presence of diltiazem at the beginning of their differentiation process into DC. Monocyte-derived DCs were stimulated with LPS, and DCs differentiated in the presence of diltiazem showed a decreased interleukin (IL)-12 production and an enhanced IL-10 production. When cultured with CD4CD45RA they were able to enhance the CD4Foxp3 T-cell population and to induce slowly proliferating T cells, which showed a significant increase of transforming growth factor (TGF)-β production. These T cells suppress proliferation of activated autologous T cells, and we show that this effect is attributable to soluble factors, primarily to TGF-β. Blockade of TGF-β by specific monoclonal antibodies reversed this inhibitory effect. Herein, we provide new evidence that diltiazem-conditioned monocyte-derived DC induce T cells which acquire a regulatory phenotype and activity similar to those described for Tregs. [ABSTRACT FROM AUTHOR]

Summary Memory T cells are known to play a key role in prevention of allograft tolerance in alloantigen-primed mice. Here, we used an adoptively transferred memory T cell model and an alloantigen-primed model to evaluate the abilities of different combinations of monoclonal antibodies (mAb) to block key signaling pathways involved in activation of effector and memory T cells. In the adoptively transferred model, the use of anti-CD134L mAb effectively prevented activation of CD4+ memory T cells and significantly prolonged islet survival, similar to the action of anti-CD122 mAb to CD8+ memory T cells. In the alloantigen-primed model, use of anti-CD134L and anti-CD122 mAbs in addition to co-stimulatory blockade with anti-CD154 and anti-LFA-1 prolonged secondary allograft survival and significantly reduced the proportion of memory T cells; meanwhile, this combination therapy increased the proportion of regulatory T cells (Tregs) in the spleen, inhibited lymphocyte infiltration in the graft, and suppressed alloresponse of recipient splenic T cells. However, we also detected high levels of alloantibodies in the serum which caused high levels of damage to the allogeneic spleen cells. Our results suggest that combination of four mAbs can significantly suppress the function of memory T cells and prolong allograft survival in alloantigen primed animals. [ABSTRACT FROM AUTHOR]

The mechanisms underlying maintenance of renal allografts in humans under minimal or conventional immunosuppression are poorly understood. There is evidence that CD4+ CD25+ regulatory T cells and clonal deletion, among other mechanisms of tolerance, could play a key role in clinical allograft survival. Twenty-four TCR-Vβ families were assessed in CD4+ CD25−, CD4+ CD25low and CD4+ CD25high T cells from patients with long-term renal allograft survival (LTS), patients exhibiting chronic rejection (ChrRx), patients on dialysis (Dial) and healthy controls (HC) by flow cytometry. LTS patients presented a higher variability in their TCR-Vβ repertoire, such decreased percentage of Vβ2+, Vβ8a+ and Vβ13+ in CD4+ CD25low and high compared with CD4+ CD25− subset and increased Vβ4 and Vβ7 families in CD4+ CD25high T cells exclusively. Additionally, LTS patients, particularly those that were not receiving calcineurin inhibitors (CNI), had increased percentages of CD4+ CD25high T cells when compared with Dial ( P < 0.05) and ChrRx ( P < 0.05) patients. Our results suggest that a differential expression of particular TCR-Vβ families and high levels of circulating CD4+ CD25high T cells in long-term surviving renal transplant patients could contribute to an active and specific state of immunologic suppression. However, the increase in this T cell subset with regulatory phenotype can be affected by CNI. [ABSTRACT FROM AUTHOR]

This prospective study assessed lymphocyte subsets in the peripheral blood of 42 islet allograft recipients using flow cytometry from 2 weeks and up to 2 years post-transplantation. Subjects received daclizumab ( n = 16), Thymoglobulin ( n = 12) or alemtuzumab ( n = 14). Alemtuzumab was associated with an early (within 1 month) and transient (up to 6 months) increase in the frequency of CD3+ CD4+ Foxp3+ T cells, while daclizumab induced a near complete loss of these cells ( P ≤ 0.001). The frequency of memory CD4+ T cells was increased following depleting immunosuppression induction with either Thymoglobulin or alemtuzumab ( P ≤ 0.05), but remained unchanged while using daclizumab. Alemtuzumab induction resulted in a significant loss of memory B lymphocytes when compared with the other induction groups ( P ≤ 0.001). While the clinical significance of these findings remains to be fully determined, the observed altered balance between effector, regulatory and memory cells suggests that the immune status of patients will be affected according to the induction strategy chosen. [ABSTRACT FROM AUTHOR]

Recently, we established a pharmacodynamic assay to monitor immunosuppressive effectiveness of cyclosporine A (CsA) in patients on standard CsA regimen. The aim of the present study was to extend this correlation to reduced CsA regimen and to compare pharmacodynamic and kinetic parameters to allow prediction of rejections and infections. In 53 heart allograft recipients, nuclear factor of activated T cells (NFAT)-regulated gene expression was quantified at trough (C0) and 2-h post-CsA dose (C2). Gene expression at C2 was calculated relative to C0 (residual gene expression, RGE) or relative to a healthy reference group (absolute gene expression, AGE). RGE correlated with CsA C2-levels in bimodal fashion: above 575 ng/ml correlation was seen with flat regression gradient. Below 575 ng/ml, correlation was excellent with markedly steeper gradient. At C0 in the low-C2 group (<575 ng/ml), AGE remained unchanged, whereas in the high-C2 group (>575 ng/ml) AGE was markedly reduced. In both groups, AGE at C2 was strongly inhibited. In patients contracting infection during follow-up, RGE was lower than in those without infections independent of CsA levels. CsA-monitoring by quantitation of NFAT-regulated gene expression is feasible with standard and reduced CsA regimens. It correlates better with the incidence of infections than measurement of CsA concentrations and might help in avoiding over-immunosuppression. [ABSTRACT FROM AUTHOR]

Chronic rejection (CR) is a major cause of long-term graft loss that would be avoided by the induction of tolerance. We previously showed that renal transplant patients with CR have lower numbers of peripheral CD4+CD25high T cells than operationally tolerant patients, patients with stable graft function and healthy volunteers (HV). We explored here the profile of CD4+CD25high blood T cells in these patients focusing on their expression of the regulatory T cells (Treg) gene Forkhead Box P3 (FOXP3) and their suppressive function. We show that CR is associated with a decreased number of CD4+CD25highFOXP3+T cells with normal regulatory profile, whereas graft acceptance is associated with CD4+CD25highFOXP3+T cell numbers similar to HVs. These data suggest that Treg numbers, rather than their intrinsic suppressive capacity, may contribute to determining the long-term fate of renal transplants. [ABSTRACT FROM AUTHOR]

The article presents abstracts of medical research. They include "Long-Term Results of ABO Incomplete Kidney Transplantation Using Antigen-Specific Immunoadsorption and Rituximab," "Effects of Rapamycin and MMF on UV-Induced Skin Carcinogenesis," and "Lymphocytes Play an Essential Role in Lung Ischemia Reperfusion Injury."

While both direct and indirect allorecognition are involved in allograft rejection, evidence to date suggests that tolerance is primarily dependent on indirect pathway-triggered CD4+CD25+ T cell-mediated immunoregulation. However, the precise influence of these two pathways on CD4+CD25+ T-cell function has not been addressed. In the current study, we have utilized an adoptive transfer model to assess selectively how the absence of either direct or indirect allorecognition affects CD4+CD25+ T-cell function. The effects of the loss of the direct pathway were assessed by transplanting skin grafts from minor histocompatibility mismatched B10.D2 (H-2d) donors onto Balb/c (H-2d) recipients, or by placing bone marrow chimeric DBA/2 (H-2d/H-2b) allografts onto C57BL/6 (H-2b) hosts. The requirement for indirect allorecognition was tested by grafting DBA/2 skin allografts onto either C57BL/6- or MHC-II-deficient C57BL/6 recipients. We report here that although CD4+CD25+ regulatory T cells can suppress both directly and indirectly generated alloresponses, immunoregulation is favored when indirect presentation is the sole mechanism of allorecognition. Hence, in the absence of indirect presentation, net CD4+CD25+ T cell-dependent immunoregulation is weak, and high ratios of CD4+CD25+ to CD4+CD25− T cells are required to ensure graft survival. [ABSTRACT FROM AUTHOR]

The activity of granzyme B, a main effector molecule of natural killer (NK) cells and cytotoxic T lymphocytes, is regulated by the intracellular serine proteinase inhibitor 9 (PI-9). Pig PI-9 was first cloned, and the sequences that encode pig PI-9, including the start codon and stop codon, were identified. The cDNA was inserted into the cloning site of pCXN2 (chicken beta actin promoter and cytomegalovirus enhancer), transfected into pig endothelial cells (PEC), and several stable PEC clones were established. An NK cell-mediated cytolysis test was next applied to the PEC clones, using YT cells (an NK-like cell line). The PEC transfectants with pig PI-9 had a significant inhibitory effect on NK cell-mediated PEC lysis. The overexpression of the anti-apoptotic molecule, pig PI-9, has the potential for use in protecting graft cells from human NK cells. [ABSTRACT FROM AUTHOR]

Vav proteins mediate T- and B-cell activation by functioning as GTP/GDP exchange factors for small GTPases. We have studied the role of Vav1 and Vav2 in allogeneic T-cell activation, antibody responses and allograft rejection. Alloantigen-induced proliferation of T cells from Vav1- and Vav1/Vav2-knockout (ko) mice was decreased by >90% in a mixed lymphocyte reaction. In whole-blood cultures, Vav deficiency led to markedly impaired T- and B-cell activation. Expansion of Vav1- or Vav1/Vav2-ko T cells (C57BL/6) was reduced after transfer into severe combined immune deficiency/beige recipient mice (BALB/c). After priming with 2,4-dinitrophenyl (DNP)–keyhole limpet hemocyanin, T-cell-dependent anti-DNP IgM and IgG antibody levels were normal in Vav1-ko mice but undetectable in Vav1/Vav2-ko mice. The median survival time of BALB/c cardiac allografts transplanted into C57BL/6 Vav1-ko mice ( n = 13) or Vav1/Vav2-ko mice ( n = 5) was >100 and >77 days, compared with 8–9 days in the corresponding wild-type mice. Vav1/Vav2-ko mice with <100 days graft survival developed bacterial skin infections and were prematurely killed with beating cardiac allograft. Long-term surviving transplants of single and double ko mice showed mild cellular interstitial rejection and mild to severe vascular remodeling. In conclusion, our studies show for the first time that the absence of Vav1 and Vav1/Vav2 in ko mice strongly reduces alloreactivity and results in long-term allograft survival, whereas antibody responses were only affected in Vav1/Vav2 ko mice. [ABSTRACT FROM AUTHOR]

Tolerance induction by mixed chimerism and costimulation blockade is a promising approach to avoid immunosuppression, but the molecular basis of tolerant T lymphocytes remains elusive. We investigated the genome-wide gene expression profile of murine T lymphocytes after tolerance induction by allogeneic bone marrow transplantation (BMT) and costimulatory blockade using the anti-CD40L antibody MR1. Molecular functions, biological processes, cellular locations, and coregulation of identified genes were determined. A total of 113 unique genes exhibited a significant differential expression between the lymphocytes of MR1-treated Tolerance (TOL ) and untreated recipients Control (CTRL ). The majority of genes upregulated in the TOL group are involved in several signal transduction cascades such as members of the MAPKKK cascade (IL6, Tob2, Stk39, and Dusp24). Other genes involved in lymphocyte differentiation and highly expressed in the TOL group are lymphotactin, the estrogen receptors (ERs) and the suppressor of cytokine signaling 7. Common transcription factors such as ER 1 alpha, GATA -binding protein 1, insulin promoter factor 1, and paired-related homeobox 2 could be identified in the promoter regions of upregulated genes in the TOL group. These data suggest that T lymphoctes of tolerant mice exhibit a distinct molecular expression profile, which needs to be evaluated in other experimental tolerance models to determine whether it is a universal signature of tolerance. [ABSTRACT FROM AUTHOR]

The article focuses on the cancer therapy where alpha (α)-bisabolol is not a matter for it. Topics includes biabolol enhanced the tumor growth factor beta 1 (TGF-B1). The organic molecules increased the TGF-B1, anti tumoral compound mass and promotes the natural killer cells. The rule of α-bisabolol on cancer therapy should be expanded and acknowledgment should also be provided.

Intracerebral haemorrhage (ICH) has no specific treatment, but accounts for up to 15% of all strokes and has the highest mortality. Fingolimod (FTY720) is an immunomodulator approved for the management of multiple sclerosis, with abundant evidence of efficacy in experimental ischemic stroke, and more limited evidence in experimental ICH. The goal of this study was to confirm the efficacy of fingolimod in experimental ICH using rigorous and statistically well-powered studies. ICH was induced in C57BL/6JOlaHsd male and female mice by intrastriatal bacterial collagenase injection. Fingolimod (0.5 mg/kg) or saline was administered intraperitoneally after 0.5, 24 and 72 h, in a randomized and blinded manner. Functional improvement with cylinder, wire hanging, and foot fault tests was evaluated one and two weeks later. Lesion volume and hemispheric atrophy were quantified at the 14-day endpoint. There was a higher mortality in saline-treated females compared to fingolimod-treated females and saline-treated males. There was no treatment- or gender-related difference in the behavioural tests. Histological outcome measures did not differ between any of the groups. These results, contrasting with those of previous studies of fingolimod in experimental ICH, emphasize the importance of rigorous testing of this agent in models more representative of the clinical situation. [ABSTRACT FROM AUTHOR]

This section introduces a series of articles about the role of protein kinase C in immune cell functions, including the physiological role of different PKC isoforms in T lymphocytes, regulation of T cell proliferation, and the process through which PKC family members regulate the formation of the microtubule organizing complex (MTOC).

The authors reflect on the activation of lymphocyte in the context of allo- and auto-immunity in the U.S. They note that on account of the increasingly sophisticated molecular and immunological tools, their knowledge of the complexities of cell-cell interaction continues to evolve. Moreover, examination of the molecular interaction that occurs when a lymphocyte encounters an antigen-presenting cell (APC) has revealed that T cells require multiple signals to become fully activated.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the novel coronavirus, causing coronavirus disease 2019 (COVID-19). During virus infection, several pro-inflammatory cytokines are produced, leading to the "cytokine storm." Among these, interleukin (IL)-6, tumor necrosis factor‐α (TNF‐α), and IL-1β seem to have a central role in the progression and exacerbation of the disease, leading to the recruitment of immune cells to infection sites. Autophagy is an evolutionarily conserved lysosomal degradation pathway involved in different aspects of lymphocytes functionality. The involvement of IL-6, TNF‐α, and IL-1β in autophagy modulation has recently been demonstrated. Moreover, preliminary studies showed that SARS-CoV-2 could infect lymphocytes, playing a role in the modulation of autophagy. Several anti-rheumatic drugs, now proposed for the treatment of COVID-19, could modulate autophagy in lymphocytes, highlighting the therapeutic potential of targeting autophagy in SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

The article presents a study conducted by R. Chris Bleackley and colleagues which describes the discovery of cloning the cytotoxic T-lymphocyte (CTL) genes. It mentions the method of the study which include killing mechanism, T cell receptor gene rearrangements, and observation on target cells which is shown to be cytolysin/perforin.

The author discusses aspects of repetitive stimulation of T cells with allogeneic lymphocytes for a long-term culture of alloreactive T cells. He highlights the stimulation of human lymphocytes with phytohemagglutinin (PHA) to promote the formation of granulocyte and monocyte colonies. He also notes that PHA-stimulated human lymphocyte will lead to long-term T-cell proliferation.