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Background: T lymphocytes in tumor microenvironment play a pivotal role in the anti-tumor immunity, and the memory of T cells contributes to the longterm protection against tumor antigens. Compared to solid tumors, studies focusing on the T-cell differentiation in the acute myeloid leukemia (AML) bone marrow (BM) microenvironment remain limited. Patients and methods: Fresh BM specimens collected from 103 adult AML patients at diagnosis and 12 healthy donors (HDs) were tested T-cell differentiation subsets by multi-parameter flow cytometry. Results: CD4 and CD8 T-cell compartments had different constituted profiles of T-cell differentiated subsets, which was similar between AML patients and HDs. Compared to HDs, AML patients as a whole had a significantly higher proportion of CD8 effector T cells (Teff, P = 0.048). Moreover, the T-cell compartment of AML patients with no DNMT3A mutations skewed toward terminal differentiation at the expense of memory T cells (CD4 Teff: P = 0.034; CD8 Teff: P = 0.030; CD8 memory T: P = 0.017), whereas those with mutated DNMT3A had a decrease in CD8 naïve T (Tn) and CD4 effector memory T cells (Tem) as well as an increase in CD4 central memory T cells (Tcm) (P = 0.037, 0.053 and 0.053). Adverse ELN genetic risk correlated with a lower proportion of CD8 Tn. In addition, the low proportions of CD4 Tem and CD8 Tn independently predicted poorer relapsefree survival (RFS, HR [95%CI]: 5.7 (1.4-22.2), P = 0.017 and 4.8 [1.3-17.4], P = 0.013) and event-free survival (EFS, HR [95% CI]: 3.3 (1.1-9.5), P = 0.029; 4.0 (1.4-11.5), P = 0.010), respectively. Conclusions: AML patients had abnormal profiles of BM T-cell differentiation subsets at diagnosis, which was related to DNMT3A mutations. The low proportions of CD4 Tem and CD8 Tn predicted poor outcomes. [ABSTRACT FROM AUTHOR]

Within the three‐dimensional (3D) nuclear space, the genome organizes into a series of orderly structures that impose important influences on gene regulation. T lymphocytes, crucial players in adaptive immune responses, undergo intricate transcriptional remodeling upon activation, leading to differentiation into specific effector and memory T cell subsets. Recent evidence suggests that T cell activation is accompanied by dynamic changes in genome architecture at multiple levels, providing a unique biological context to explore the functional relevance and molecular mechanisms of 3D genome organization. Here, we summarize recent advances that link the reorganization of genome architecture to the remodeling of transcriptional programs and conversion of cell fates during T cell activation and differentiation. We further discuss how various chromatin architecture regulators, including CCCTC‐binding factor and several transcription factors, collectively modulate the genome architecture during this process. [ABSTRACT FROM AUTHOR]

No clear consensus has emerged from the literature on the gene expression changes that occur in human whole blood with age. In this study we compared whole blood ageing genes from the published literature with data on gene specificity for leukocyte subtypes. Surprisingly we found that highly ranked ageing genes were predominantly expressed by naïve T cells, with limited expression from more common cell types. Highly ranked ageing genes were also more likely to have decreased expression with age. Taken together, it is plausible that much of the observed gene expression changes in whole blood is reflecting the decline in abundance of naïve T cells known to occur with age, rather than changes in transcription rates in common cell types. Correct attribution of the gene expression changes that occur with age is essential for understanding the underlying mechanisms. [ABSTRACT FROM AUTHOR]

Myeloid-Derived Suppressor Cells (MDSCs), also known as 'Natural Suppressor Cells (NSCs)', 'Immature Myeloid Cells, (IMCs), or 'Myeloid Suppressor Cells' (MSCs), are renowned for suppressing the immune functioning of T lymphocytes. Depending on the structural similarity with neutrophils and monocytes, MDSCs can be classified as polymorphonuclear MDSCs (PMN-MDSCs) and monocytic MDSCs (M-MDSCs). On the other hand, T cells, generally subdivided into CD4+ and CD8+ groups based on the surface glycoprotein, are crucial for generating an adaptive immune response. During the event of an infection, MDSCs and T cells, along with other immune regulatory cells, interplay and generate a robust host immune response against the invading pathogens. In this review, we have highlighted the role of MDSCs and different subsets of CD4+ T cells, such as Th1, Th2, Th17, Th9, Th22, Treg, Tfh, and Tr1 with and various transcription factors associated with them, in different well known bacterial, viral, parasitic and fungal diseases. Changes in the MDSC population were found to be associated with either promotion or suppression of T cell subsets in different infections. The relative frequency and absolute numbers of MDSCs in the peripheral blood, therefore, may serve as an important marker useful in future immunotherapeutics. [ABSTRACT FROM AUTHOR]

No clear consensus has emerged from the literature on the gene expression changes that occur in human whole blood with age. In this study we compared whole blood ageing genes from the published literature with data on gene specificity for leukocyte subtypes. Surprisingly we found that highly ranked ageing genes were predominantly expressed by naïve T cells, with limited expression from more common cell types. Highly ranked ageing genes were also more likely to have decreased expression with age. Taken together, it is plausible that much of the observed gene expression changes in whole blood is reflecting the decline in abundance of naïve T cells known to occur with age, rather than changes in transcription rates in common cell types. Correct attribution of the gene expression changes that occur with age is essential for understanding the underlying mechanisms.

CCL21‐Ser, a chemokine encoded by the Ccl21a gene, is constitutively expressed in the thymic epithelial cells and stromal cells of secondary lymphoid organs. It regulates immune cell migration and survival through its receptor CCR7. Herein, using CCL21‐Ser‐expressing melanoma cells and the Ccl21a‐deficient mice, we demonstrated the functional role of cancer cell‐derived CCL21‐Ser in melanoma growth in vivo. The B16‐F10 tumor growth was significantly decreased in Ccl21a‐deficient mice compared with that in wild‐type mice, indicating that host‐derived CCL21‐Ser contributes to melanoma proliferation in vivo. In Ccl21a‐deficient mice, tumor growth of melanoma cells expressing CCL21‐Ser was significantly enhanced, suggesting that CCL21‐Ser from melanoma cells promotes tumor growth in the absence of host‐derived CCL21‐Ser. The increase in tumor growth was associated with an increase in the CCR7+ CD62L+ T cell frequency in the tumor tissue but was inversely correlated with Treg frequency, suggesting that naïve T cells primarily promote tumor growth. Adoptive transfer experiments demonstrated that naïve T cells are preferentially recruited from the blood into tumors with melanoma cell‐derived CCL21‐Ser expression. These results suggest that CCL21‐Ser from melanoma cells promotes the infiltration of CCR7+ naïve T cells into the tumor tissues and creates a tumor microenvironment favorable for melanoma growth. [ABSTRACT FROM AUTHOR]

BackgroundIn 6.5 years of newborn screening for severe combined immunodeficiency in California, 3,252,156 infants had DNA from dried blood spots (DBSs) assayed for T-cell receptor excision circles. Infants with T-cell receptor excision circle values of less than a designated cutoff on a single DBS, 2 DBS samples with insufficient PCR amplification, or known genetic risk of immunodeficiency had peripheral blood complete blood counts and lymphocyte subsets assayed in a single flow cytometry laboratory. Cases in which immune defects were ruled out were available for analysis.ObjectiveWe sought to determine reference intervals for lymphocyte subsets in racially/ethnically diverse preterm and term newborns who proved to be unaffected by any T-lymphopenic immune disorder.MethodsEffective gestational age (GA) was defined as GA at birth plus postnatal age at the time of sample collection. After determining exclusion criteria, we analyzed demographic and clinical information, complete and differential white blood cell counts, and lymphocyte subsets for 301 infants, with serial measurements for 33 infants. Lymphocyte subset measurements included total T cells, helper and cytotoxic T-cell subsets, naive and memory phenotype of each T-cell subset, B cells, and natural killer cells.ResultsReference intervals were generated for absolute numbers and lymphocyte subsets from infants with effective GAs of 22 to 52 weeks. Sex and ethnicity were not significant determinants of lymphocyte subset counts in this population. Lymphocyte counts increased postnatally.ConclusionThis study provides a baseline for interpreting comprehensive lymphocyte data in preterm and term infants, aiding clinicians to determine which newborns require further evaluations for immunodeficiency.

Naive CD4+ T cells are an example of dynamic cell homeostasis: T cells need to avoid autoreactivity while constantly seeing self-peptides, yet they must be primed to react to foreign antigens during infection. The instructive signals that balance this primed yet quiescent state are unknown. Interactions with self-peptides result in membrane-proximal, tonic signals in resting T cells. Here we reveal selective and robust tonic mTORC1 signals in CD4+ T cells that influence T cell fate decisions. We find that the Ras exchange factor Rasgrp1 is necessary to generate tonic mTORC1 signals. Genome-wide ribosome profiling of resting, primary CD4+ T cells uncovers a baseline translational landscape rich in mTOR targets linked to mitochondria, oxidative phosphorylation, and splicing. Aberrantly increased tonic mTORC1 signals from a Rasgrp1Anaef allele result in immunopathology with spontaneous appearance of T peripheral helper cells, follicular helper T cells, and anti-nuclear antibodies that are preceded by subtle alterations in the translational landscape.

Special AT‐binding protein 1 (SATB1) is a chromatin‐binding protein that has been shown to be a key regulator of T‐cell development and CD4+ T‐cell fate decisions and function. The underlying function for SATB1 in peripheral CD8+ T‐cell differentiation processes is largely unknown. To address this, we examined SATB1‐binding patterns in naïve and effector CD8+ T cells demonstrating that SATB1 binds to noncoding regulatory elements linked to T‐cell lineage–specific gene programs, particularly in naïve CD8+ T cells. We then assessed SATB1 function using N‐ethyl‐N‐nitrosourea‐mutant mice that exhibit a point mutation in the SATB1 DNA‐binding domain (termed Satb1m1Anu/m1Anu). Satb1m1Anu/m1Anu mice exhibit diminished SATB1‐binding, naïve, Satb1m1Anu/m1Anu CD8+ T cells exhibiting transcriptional and phenotypic characteristics reminiscent of effector T cells. Upon activation, the transcriptional signatures of Satb1m1Anu/m1Anu and wild‐type effector CD8+ T cells converged. While there were no overt differences, primary respiratory infection of Satb1m1Anu/m1Anu mice with influenza A virus (IAV) resulted in a decreased proportion and number of IAV‐specific CD8+ effector T cells recruited to the infected lung when compared with wild‐type mice. Together, these data suggest that SATB1 has a major role in an appropriate transcriptional state within naïve CD8+ T cells and ensures appropriate CD8+ T‐cell effector gene expression upon activation. [ABSTRACT FROM AUTHOR]

Naive CD4+ T cells in specific pathogen-free (SPF) mice are characterized by transcriptional heterogeneity and subpopulations distinguished by the expression of quiescence, the extracellular matrix (ECM) and cytoskeleton, type I interferon (IFN-I) response, memory-like, and T cell receptor (TCR) activation genes. We demonstrate that this constitutive heterogeneity, including the presence of the IFN-I response cluster, is commensal independent insofar as being identical in germ-free and SPF mice. By contrast, Nippostrongylus brasiliensis infection altered this constitutive heterogeneity. Naive T cell-intrinsic transcriptional changes acquired during helminth infection correlated with and accounted for decreased immunization response to an unrelated antigen. These compositional and functional changes were dependent variables of helminth infection, as they disappeared at the established time point of its clearance in mice. Collectively, our results indicate that the naive T cell pool is subject to dynamic transcriptional changes in response to certain environmental cues, which in turn permutes the magnitude of the immune response. [Display omitted] • Naive CD4+ T cell transcriptional heterogeneity is commensal independent • Helminth infection recasts the basal transcriptional profile • These transient, IL-4-dependent changes correspond to the period of active infection • Helminth-induced changes correlate with suppressed activation of bystander T cells The discovery of naive CD4+ T cell transcriptional heterogeneity raises the question regarding its plasticity and the mechanisms that may perturb the basal state. Even et al. report that, in mice, helminth infection, but not commensal colonization, transiently recasts this amalgam to dampen bystander T cell activation during active disease. [ABSTRACT FROM AUTHOR]

Naïve T and T memory cell subsets are closely related to immune response and can provide important information for the diagnosis and treatment of immunological and hematological disorders. Lymphocyte compartment undergoes dramatic changes during adulthood; age-related reference values derived from healthy individuals are crucial. However, extensively detailed reference values of peripheral blood lymphocytes in the whole spectrum of adulthood detected by multi-color flow cytometry on a single platform are rare. Three hundred and nine healthy adult volunteers were recruited from Tianjin in China. The absolute counts and percentages of CD3+CD4+ T cells, CD3+CD8+ T cells, naïve T cells (Tn), T memory stem cells (Tscm), central memory T cells (Tcm), effector memory T cells (Tem), and terminal effector T cells (Tte) were detected by flow cytometry with single platform technologies. Reference range of absolute counts and percentage of T lymphocyte subsets were formulated by different age and gender. The results showed that Tn and Tscm cells, which had stem cell properties, decreased with aging; while, Tcm and Tem increased with aging, which increased from 18 to 64 years old but presented no significant change over the 65 years old. Gender had an influence on the fluctuation of lymphocyte subsets, the absolute count of CD3+CD8+, CD8+Tcm, CD8+Tem in males were higher than those in females. The reference values of percentages and absolute numbers of naïve T and T memory cell subsets can help doctors to understand the immune state of patients and evaluate conditions of prognosis then adjust the treatment for patients. (Chinese Clinic Trial Registry number: ChiCTR-IOR-17014139.) The absolute counts and percentages of CD3+CD4+ T cells, CD3+CD8+ T cells, naïve T cells (Tn), T memory stem cells (Tscm), central memory T cells (Tcm), effector memory T cells (Tem), terminal effector T cells (Tte) were detected by flow cytometry with single platform technologies. Reference range of absolute counts and percentage of T lymphocyte subsets were formulated by different age and gender. Gender and age had influence on the absolute counts of T lymphocyte subsets. [ABSTRACT FROM AUTHOR]

Objective To investigate the role of programmed cell death protein 1 (PD-1) and its two ligands, PD-L1 and PD-L2, in the pathogenesis of IgG4-related disease (IgG4-RD). Methods Patients with IgG4-RD (n  = 43) and healthy controls (n  = 34) were recruited. Expression levels of PD-1, PD-L1 and PD-L2 in plasma, submandibular gland and T cell subsets were determined by ELISA, immunohistochemistry and flow cytometry. Naïve T cells were stimulated with or without PD-L1/PD-L2 or anti-PD-L1/anti-PD-L2 for 7 days and the proportion of CD4+CD25+ Treg cells was detected by flow cytometry. Results The expression of PD-1, PD-L1 and PD-L2 in the plasma, submandibular gland and on the surface of Treg cells was increased in IgG4-RD patients. Plasma soluble (s)PD-1 was positively correlated with serum IgG, IgG1, IgG3, IgG4, IgG4-RD responder index and numbers of organs involved, and negatively correlated with serum IgM, IgA, C3 and C4. Plasma sPD-L2 was positively correlated with serum IgG1, and plasma sPD-L1 was positively correlated with sPD-L2 and negatively correlated with C3. Stimulation of PD-L1 but not PD-L2 promoted the differentiation of naïve T cells from IgG4-RD patients into CD4+CD25+ Treg cells. Conclusion Plasma concentrations of sPD-1, sPD-L1 and sPD-L2 were significantly increased in patients with IgG4-RD, and the expression of PD-1 and PD-L2 on Treg cells was upregulated. PD-1–PD-L1 can promote the differentiation of naïve T cells into Treg cells and thus participate in the pathogenesis of IgG4-RD. [ABSTRACT FROM AUTHOR]

Memory T cells are crucial players in vertebrate adaptive immunity but their development is incompletely understood. Here, we describe a method to produce human memory-like T cells from naive human T cells in culture. Using commercially available human T-cell differentiation kits, both purified naive CD8+ T cells and purified naive CD4+ T cells were activated via T-cell receptor signaling and appropriate cytokines for several days in culture. All the T-cell activators were then removed from the medium and the cultures were continued in hypoxic condition (1% O2 atmosphere) for several more days; during this period, most of the cells died, but some survived in a quiescent state for a month. The survivors had small round cell bodies, expressed differentiation markers characteristic of memory T cells and restarted proliferation when the T-cell activators were added back. We could also induce memory-like T cells from naive human T cells without hypoxia, if we froze the activated T cells or prepared the naive T cells from chilled filter buffy coats. Pre-activated human naïve CD4+ or CD8+ T cells were cultured in activator-free medium to induce cell death for 5 to 10 days. Although no cell survived in normal oxygen condition (20% O2), 2 to 30% of the activated T cells could survive in hypoxia (1% O2) and became memory-like T cells. We named this simple procedure as 'the Death Assay'. [ABSTRACT FROM AUTHOR]

Background: T lymphocytes in tumor microenvironment play a pivotal role in the anti-tumor immunity, and the memory of T cells contributes to the long-term protection against tumor antigens. Compared to solid tumors, studies focusing on the T-cell differentiation in the acute myeloid leukemia (AML) bone marrow (BM) microenvironment remain limited., Patients and Methods: Fresh BM specimens collected from 103 adult AML patients at diagnosis and 12 healthy donors (HDs) were tested T-cell differentiation subsets by multi-parameter flow cytometry., Results: CD4 and CD8 T-cell compartments had different constituted profiles of T-cell differentiated subsets, which was similar between AML patients and HDs. Compared to HDs, AML patients as a whole had a significantly higher proportion of CD8 effector T cells (Teff, P = 0.048). Moreover, the T-cell compartment of AML patients with no DNMT3A mutations skewed toward terminal differentiation at the expense of memory T cells (CD4 Teff: P = 0.034; CD8 Teff: P = 0.030; CD8 memory T: P = 0.017), whereas those with mutated DNMT3A had a decrease in CD8 naïve T (Tn) and CD4 effector memory T cells (Tem) as well as an increase in CD4 central memory T cells (Tcm) ( P = 0.037, 0.053 and 0.053). Adverse ELN genetic risk correlated with a lower proportion of CD8 Tn. In addition, the low proportions of CD4 Tem and CD8 Tn independently predicted poorer relapse-free survival (RFS, HR [95%CI]: 5.7 (1.4-22.2), P = 0.017 and 4.8 [1.3-17.4], P = 0.013) and event-free survival (EFS, HR [95% CI]: 3.3 (1.1-9.5), P = 0.029; 4.0 (1.4-11.5), P = 0.010), respectively., Conclusions: AML patients had abnormal profiles of BM T-cell differentiation subsets at diagnosis, which was related to DNMT3A mutations. The low proportions of CD4 Tem and CD8 Tn predicted poor outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Sun, Shi, Wang, Xie, Liu, Jiang, Jiang, Huang and Qin.)

Blinatumomab, a CD19/CD3 bispecific T-cell engager, is recognized as an effective immunotherapy for relapsed B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, the efficacy and safety of blinatumomab in post-hematopoietic stem cell transplantation (HSCT) maintenance therapy has not been established. A 5-year-old male patient with BCP-ALL suffered a relapse in his bone marrow during maintenance therapy. After re-induction therapy with UK-R3 regimen, 2.3% of the blasts remained. Then the blinatumomab was administered, and he achieved minimal residual disease (MRD)-negative complete remission (CR). After two cycles of blinatumomab, he underwent allogeneic bone marrow transplantation (BMT) from his human leukocyte antigen (HLA)-matched sibling, following conditioning with total body irradiation, etoposide, and cyclophosphamide. Two cycles of blinatumomab maintenance therapy were initiated to prevent relapse. There was no exacerbation of graft-versus-host disease (GVHD) or other severe adverse events. CR was maintained for >22 months after BMT. A t-distributed symmetric neighbor embedding (tSNE) analysis revealed that blinatumomab altered the CD8+ population, as with pre-HSCT use, and markedly reduced the CD8+19dim+/CD8+CD19- ratio (i.e., naïve lymphocyte predominance). Blinatumomab maintenance therapy after HSCT may be considered a safe treatment., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Ethics Committee on Clinical Research, Sakuragaoka Campus, Kagoshima University issued approval 230260. Informed consent was obtained from the patient and his parents to publish this case report. The case report was approved by the Ethics Committee on Clinical Research, Sakuragaoka Campus, Kagoshima University (approval number: 230260). Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Abematsu et al.)

Autophagy is highly regulated and plays a multitude of roles during T cell-mediated immune responses. It has been shown that autophagy deficiency in T cells results in a decrease in total T cells, including naïve T cells in young mice, but the mechanism is still not understood. Here, similar to what happened in young mice, we showed that T cell-specific deletion of Beclin 1/Atg6 (Becn1 −/−) resulted in decreases in the percentages of CD4+, CD8+, and regulatory T cells in adult mice. In addition, we found that the effector to naïve T cell ratio was increased in older mice. Also, as mice grew older, Becn1 −/− mice progressively lost weight and developed severe colitis. Analysis of inflamed tissues demonstrated increases in the portion and cytokine production of effector T cells. In contrast, the TCR-transgenic Becn1 −/− mice had similar numbers of naïve T cells compared to WT controls. Similar to bulk T cells, the TCR-transgenic Becn1 −/− T cells generated much lower numbers of effector T cells compared to WT controls after activation in vitro. These data suggest that autophagy is not required for maintaining the naïve T cell but required for the generation of effector T cells in vivo.

Prior experiments in explants of human lymphoid tissue have demonstrated that human immunodeficiency virus type 1 (HIV-1) productively infects diverse cellular targets including T cells and tissue macrophages. We sought to determine the specific contribution of macrophages and T cells to the overall viral burden within lymphoid tissue. To block infection of macrophages selectively while preserving infection of T cells, we used viruses deficient for viral protein R (Vpr) that exhibit profound replication defects in nondividing cells in vitro. We inoculated tonsil histocultures with matched pairs of congenic viruses that differed only by the presence of a wild-type or truncated vpr gene. Although these viruses exhibited no reduction in the infection or depletion of T cells, the ability of the Vpr-deficient R5 virus to infect tissue macrophages was severely impaired compared with matched wild-type R5 virus. Interestingly, the Vpr-deficient R5 virus also exhibited a 50% reduction in overall virus replication compared with its wild-type counterpart despite the fact that macrophages represent a small fraction of the potential targets of HIV-1 infection in these tissues. Collectively, these data highlight the importance of tissue macrophages in local viral burden and further implicate roles for CC chemokine receptor 5, macrophages, and Vpr in the life cycle and pathogenesis of HIV-1.

The success of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the treatment of hematological malignancies remains hampered by life-threatening chronic graft vs. host disease (cGVHD). Although multifactorial in nature, cGVHD has been associated with imbalances between effector and regulatory T cells (Treg). To further elucidate this issue, we performed a prospective analysis of patients undergoing unrelated donor allo-HSCT after a reduced intensity conditioning (RIC) regimen containing anti-thymocyte globulin (ATG) and the same GVHD prophylaxis, at a single institution. We studied T cell subset homeostasis over a 24-month follow-up after HSCT in a comparative analysis of patients with and without cGVHD. We also quantified naive and memory T cell subsets, proliferation and expression of the apoptosis-related proteins Bcl-2 and CD95. Finally, we assessed thymic function by T cell receptor excision circle (TREC) quantification and T cell receptor (TCR) diversity by TCRVβ spectratyping. While the total number of conventional CD4 (Tcon) and CD8 T cells was similar between patient groups, Treg were decreased in cGVHD patients. Interestingly, we also observed divergent patterns of Naive and Stem Cell Memory (SCM) subset recovery in Treg and Tcon compared to CD8. Patients with cGVHD showed impaired recovery of Naive and SCM Tcon and Treg, but significantly increased frequencies and absolute numbers of Naive and SCM were observed in the CD8 pool. Markedly increased EMRA CD8 T cells were also noted in cGVHD. Taken together, these results suggest that Naive, SCM and EMRA CD8 play a role in the emergence of cGHVD. Reduced Naive and recent thymic emigrant Tcon and Treg in cGVHD was likely due to impaired thymic output, as it was accompanied by decreased CD4 TREC and TCR diversity. On the other hand, CD8 TCR diversity was similar between patient groups. Furthermore, no correlation was observed between CD8 TREC content and Naive CD8 numbers, suggesting limited thymic production of Naive CD8 T cells in patients after transplant, especially in those developing cGVHD. The mechanisms behind the opposing patterns of CD4 and CD8 subset cell recovery in cGVHD remain elusive, but may be linked to thymic damage associated with the conditioning regimen and/or acute GVHD.

The adaptive immune system uses several strategies to generate a repertoire of T cell receptors (TCR) with sufficient diversity to recognize the universe of potential pathogens. However, it remains unclear how differences in the T cell receptor (TCR) contribute to heterogeneity in T cell state. In this study, we used polychromatic flow cytometry to isolate highly pure CD4+/CD8+ naive and memory T cells, and applied deep sequencing to characterize corresponding TCR β-chain (TCRβ) complementary-determining region 3 (CDR3) repertoires. We find that shorter TCRβ CDR3s with fewer insertions were highly enriched during thymic selection. Antigen-experienced T cells (memory T cells) harbor shorter CDR3s vs. naive T cells. Moreover, the public TCRβ CDR3 clonotypes within cell subsets or interindividual tend to have shorter CDR3 length and a significantly larger size compared with “private” clonotypes. Taken together, shorter CDR3s highly enriched during thymic selection and antigen-driven selection, and further enriched in public T-cell responses. These results indicated that it may be evolutionary pressures drive short CDR3s to recognize most of antigen in nature.

Chimeric antigen receptors (CAR) are synthetic receptors engineered to target a user-defined antigen. They comprise an extracellular single-chain variable fragment for target recognition and intracellular signalling domains commonly derived from immune cells. CAR-T cells have proven to be successful in therapy of some cancers. CAR-T cells are activated upon antigen-priming and subsequent intracellular signalling. However, tonic signalling in CAR-T cells remains a challenge in developing CAR-T therapeutics of high efficacy as it causes early T-cell exhaustion, limiting therapeutic persistence. Moreover, a poor choice of target antigen leads to off-target cytotoxicity, often hampering the host's survival. In addition, conventional methods of delivering CAR gene circuits utilise viral vectors, such as lentiviruses and retroviruses, which insert the CAR gene circuits into transcriptionally active sites in the genome. This increases the risks of malignant transformation due to improper genome integration. Optimisation in CAR-T engineering, from the architecture of CAR gene circuits to the structure of CAR and the behaviour of CAR-T cells, is paramount to ensure high efficacy, persistence, and precision in CAR-T therapy. This review provides insights into engineering CAR-T cells for precision in cancer therapy by highlighting the key strategies recently developed to optimise the function and efficiency of CARs. The delivery method of CAR gene circuits, circuit and structural modification of CAR, T-cell phenotype manipulation and T-cell arming will be discussed to accentuate their interplay in regulating CAR-T therapy's safety, precision, and efficacy., (Copyright © 2024. Published by Elsevier Inc.)

The success of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the treatment of hematological malignancies remains hampered by life-threatening chronic graft vs. host disease (cGVHD). Although multifactorial in nature, cGVHD has been associated with imbalances between effector and regulatory T cells (Treg). To further elucidate this issue, we performed a prospective analysis of patients undergoing unrelated donor allo-HSCT after a reduced intensity conditioning (RIC) regimen containing anti-thymocyte globulin (ATG) and the same GVHD prophylaxis, at a single institution. We studied T cell subset homeostasis over a 24-month follow-up after HSCT in a comparative analysis of patients with and without cGVHD. We also quantified naive and memory T cell subsets, proliferation and expression of the apoptosis-related proteins Bcl-2 and CD95. Finally, we assessed thymic function by T cell receptor excision circle (TREC) quantification and T cell receptor (TCR) diversity by TCRVβ spectratyping. While the total number of conventional CD4 (Tcon) and CD8 T cells was similar between patient groups, Treg were decreased in cGVHD patients. Interestingly, we also observed divergent patterns of Naive and Stem Cell Memory (SCM) subset recovery in Treg and Tcon compared to CD8. Patients with cGVHD showed impaired recovery of Naive and SCM Tcon and Treg, but significantly increased frequencies and absolute numbers of Naive and SCM were observed in the CD8 pool. Markedly increased EMRA CD8 T cells were also noted in cGVHD. Taken together, these results suggest that Naive, SCM and EMRA CD8 play a role in the emergence of cGHVD. Reduced Naive and recent thymic emigrant Tcon and Treg in cGVHD was likely due to impaired thymic output, as it was accompanied by decreased CD4 TREC and TCR diversity. On the other hand, CD8 TCR diversity was similar between patient groups. Furthermore, no correlation was observed between CD8 TREC content and Naive CD8 numbers, suggesting limited thymic production of Naive CD8 T cells in patients after transplant, especially in those developing cGVHD. The mechanisms behind the opposing patterns of CD4 and CD8 subset cell recovery in cGVHD remain elusive, but may be linked to thymic damage associated with the conditioning regimen and/or acute GVHD. [ABSTRACT FROM AUTHOR]

The adaptive immune system uses several strategies to generate a repertoire of T cell receptors (TCR) with sufficient diversity to recognize the universe of potential pathogens. However, it remains unclear how differences in the T cell receptor (TCR) contribute to heterogeneity in T cell state. In this study, we used polychromatic flow cytometry to isolate highly pure CD4+/CD8+ naive and memory T cells, and applied deep sequencing to characterize corresponding TCR β-chain (TCRβ) complementary-determining region 3 (CDR3) repertoires. We find that shorter TCRβ CDR3s with fewer insertions were highly enriched during thymic selection. Antigen-experienced T cells (memory T cells) harbor shorter CDR3s vs. naive T cells. Moreover, the public TCRβ CDR3 clonotypes within cell subsets or interindividual tend to have shorter CDR3 length and a significantly larger size compared with "private" clonotypes. Taken together, shorter CDR3s highly enriched during thymic selection and antigen-driven selection, and further enriched in public T-cell responses. These results indicated that it may be evolutionary pressures drive short CDR3s to recognize most of antigen in nature. [ABSTRACT FROM AUTHOR]

The disruption of adaptive immune response has adverse effects on the establishment and maintenance of pregnancy. The adaptive immune system is regulated by several types of immune cells. However, there is limited information about cell hierarchy in the adaptive immune response to the establishment and maintenance of pregnancy in women. The assessment of the outcome of pregnancy in primary immunodeficiency diseases could help in understanding the cell hierarchy in the adaptive immune system during pregnancy. Common variable immunodeficiency (CVID) is a heterogeneous adaptive immune system disorder characterized by primary hypogammaglobulinemia. A few studies have previously reported the assessment of the T and B cell subpopulations in CVID patients. However, an assessment of the subpopulations of T and B cells and the outcome of pregnancy in women with CVID has not been reported till date. Most CVID patients show a general decrease in the expression of CD27 in B cells. The assessment of pregnancy and the subpopulations of T and B cells in CVID women with severe reduction in the naïve T and switched B cells could help understand whether these cells are essential for the establishment and maintenance of pregnancy in women. [ABSTRACT FROM AUTHOR]

Abstract: Interferon regulatory factor 4 (IRF4) regulates the clonal expansion and metabolic activity of activated T cells, but the precise context and mechanisms of its function in these processes are unclear. In this issue of the European Journal of Immunology, Miyakoda et al. [Eur. J. Immunol. 2018. 48: 1319–1328] show that IRF4 is required for activation and expansion of naïve and memory CD8+ T cells driven by T‐cell receptor (TCR) signaling, but dispensable for memory CD8+ T‐cell maintenance and homeostatic proliferation driven by homeostatic cytokines. The authors show that the function of IRF4 in CD8+ T‐cell expansion is partially dependent upon activation of the PI3K/AKT pathway through direct or indirect attenuation of PTEN expression. These data shed light upon the differential intracellular pathways required for naïve and memory T cells to respond to self‐antigens and/or homeostatic cytokines, and highlight the potential translational relevance of these findings in the context of immune reconstitution such as following allogeneic stem cell transplantation. [ABSTRACT FROM AUTHOR]

CD28H is a newly discovered co-receptor of the human B7 family. CD28H interacts with its ligand B7-H5 and regulates T cell response. Here we showed that CD28H was not expressed on granulocytes, monocytes, myeloid dendritic cells (MDCs), and B cells, but constitutively expressed with moderate levels on memory T cells and with high levels on naïve T cells, innate lymphoid cells (ILCs), natural killer (NK) cells, and plasmacytoid dendritic cells (PDCs) in human peripheral blood. Similar CD28H+ cell profile existed in secondary lymphoid organs and pathological tissues including multiple types of cancers. Further analysis demonstrated that CD28H+ naïve and CD28H+ memory T cells were characterized with increased naïve feature and less effector functional phenotype, respectively. High levels of constitutive CD28H expression on naïve T cells and innate immune cells suggest a potential role of CD28H in innate and adaptive immunity.

Dysregulation of interleukin-22 (IL-22) has been associated with autoimmune diseases but divergent effects upon inflammation have hampered efforts to define its contribution to pathogenesis. Here, we examined the role of IL-22 in patients with psoriatic arthritis (PsA). In the peripheral blood of PsA patients, there was a decrease in IL-22+CD4+ T cells compared with healthy controls resulting in a heightened CD4+ IFNγ+/IL-22+ ratio accompanied by diminished CCR6 expression. IL-22 expressing cells were depleted primarily from the central memory CD4 T-cell subset in PsA patients. Paradoxically IL-22 and particularly interferon-gamma (IFNγ) production were elevated within a CD4+ T-cell subset with phenotypic markers characteristic of naïve T cells (CD3+CD4+CD27+CD45RA+CCR7+CD95−IL-2Rβ−) from PsA patients with the highest IFNγ+/IL-22+ ratio of all the CD4 subsets. These unconventional “naïve” CD4+ T cells from PsA patients displayed some phenotypic and functional characteristics of memory cells including a marked proliferative response. Increased IFNγ production from these unconventional “naïve” T cells from PsA patients promoted greater expression of the chemo-attractant CXCL9 by HaCaT keratinocytes compared with their healthy counterparts. Treatment with anti-TNF therapy reversed these abnormalities in this T-cell subset though did not affect the frequency of IL-22+ T cells overall. Furthermore, blockade of IL-22 enhanced the IFNγ mediated release of CXCL-9. These results reveal CD4+ T-cell dysregulation in patients with PsA which can be reversed by anti-TNF and highlight the regulatory properties of IL-22 with important implications for therapeutic approaches that inhibit its production.

Purpose: Cerebrovascular complications, including ischemic stroke, account for poor outcomes in patients on hemodialysis. T cell responses may be involved in the pathogenesis of ischemic stroke. We aimed to evaluate the role of naïve T cells in development of ischemic stroke in patients on hemodialysis. Methods: In this cross-sectional study, 156 patients on hemodialysis in our blood purification center were included. These patients were divided into the ischemic stroke (IS) group (61 cases) and non-ischemic stroke (non-IS) group (95 cases) according to a new diagnosis after initiation of hemodialysis. After being lysed with red blood cell lysis solution, peripheral blood was tested by flow cytometry to detect the expression of CD45RO and CCR7 in CD4 T and CD8 T cells. Correlation analysis and logistic regression analysis were conducted to identify potential independent risk factors for ischemic stroke. Results: The percentage of peripheral naïve T cells was lower in the IS group [median (interquartile range (IQR)) 13.9% (8.6-22.9%)] compared with the non-IS group [median (IQR) 22.7% (15.9-32.2%), P < 0.001]. Spearman correlation analysis showed that naïve T cells were negatively associated with ischemic stroke ( r = −0.308, P < 0.001). Multivariate logistic regression analysis showed that CD4 naïve T cells had an independent negative association with ischemic stroke in patients on hemodialysis (odds ratio 0.933, 95% CI 0.883, 0.986; P = 0.013). Conclusion: A decrease in percentage of peripheral CD4 naïve T cells is a risk factor for ischemic stroke in patients on hemodialysis. [ABSTRACT FROM AUTHOR]

Dysregulation of interleukin-22 (IL-22) has been associated with autoimmune diseases but divergent effects upon inflammation have hampered efforts to define its contribution to pathogenesis. Here, we examined the role of IL-22 in patients with psoriatic arthritis (PsA). In the peripheral blood of PsA patients, there was a decrease in IL-22+CD4+ T cells compared with healthy controls resulting in a heightened CD4+ IFNγ+/IL-22+ ratio accompanied by diminished CCR6 expression. IL-22 expressing cells were depleted primarily from the central memory CD4 T-cell subset in PsA patients. Paradoxically IL-22 and particularly interferon-gamma (IFNγ) production were elevated within a CD4+ T-cell subset with phenotypic markers characteristic of naïve T cells (CD3+CD4+CD27+CD45RA+CCR7+CD95-IL-2Rβ-) from PsA patients with the highest IFNγ+/IL-22+ ratio of all the CD4 subsets. These unconventional "naïve" CD4+ T cells from PsA patients displayed some phenotypic and functional characteristics of memory cells including a marked proliferative response. Increased IFNγ production from these unconventional "naïve" T cells from PsA patients promoted greater expression of the chemo-attractant CXCL9 by HaCaT keratinocytes compared with their healthy counterparts. Treatment with anti-TNF therapy reversed these abnormalities in this T-cell subset though did not affect the frequency of IL-22+ T cells overall. Furthermore, blockade of IL-22 enhanced the IFNγ mediated release of CXCL-9. These results reveal CD4+ T-cell dysregulation in patients with PsA which can be reversed by anti-TNF and highlight the regulatory properties of IL-22 with important implications for therapeutic approaches that inhibit its production. [ABSTRACT FROM AUTHOR]

Objective: To evaluate cluster of differentiation (CD)127 expression in T cells of patients with HIV-1 and the relationship of CD127 expression with disease progression. Methods: We divided 139 patients infected with human immunodeficiency virus type 1 (HIV-1) who had undergone highly active antiretroviral therapy (HAART) into 3 groups: patients with poor recovery (CD4+T<350/mL, patients with general recovery (CD4+ T= 350 - ~600/µL) and patients with good recovery (CD4+ T>600/µL). Counts and percentages of naïve (CD45RA+) and memory (CD45RO+) T cells and CD127 expression were determined using flow cytometry. Results: CD4+ CD45RO+, CD4+ CD45RA+, CD4+ CD45RO+ CD127+, and CD4+ CD45RA+ CD127+ T-cell counts in patients with good recovery were higher than in patients with poor recovery and those with general recovery patients (P <.05). Percentages of CD45RO+ were increased, and percentages of CD45RA+ and CD127 in T cells were decreased in patients with poor and general recovery (P <.05). CD127 values were positively correlated with CD4+ T-cell counts and percentages of CD45RA+ subsets (P <.05). Conclusion: CD127 expression in T cells is decreased in patients with HIV-1 and is related to recovery of CD4+ T-cell counts and to naïve subsets. [ABSTRACT FROM AUTHOR]

CCL21-Ser, a chemokine encoded by the Ccl21a gene, is constitutively expressed in the thymic epithelial cells and stromal cells of secondary lymphoid organs. It regulates immune cell migration and survival through its receptor CCR7. Herein, using CCL21-Ser-expressing melanoma cells and the Ccl21a-deficient mice, we demonstrated the functional role of cancer cell-derived CCL21-Ser in melanoma growth in vivo. The B16-F10 tumor growth was significantly decreased in Ccl21a-deficient mice compared with that in wild-type mice, indicating that host-derived CCL21-Ser contributes to melanoma proliferation in vivo. In Ccl21a-deficient mice, tumor growth of melanoma cells expressing CCL21-Ser was significantly enhanced, suggesting that CCL21-Ser from melanoma cells promotes tumor growth in the absence of host-derived CCL21-Ser. The increase in tumor growth was associated with an increase in the CCR7 + CD62L + T cell frequency in the tumor tissue but was inversely correlated with Treg frequency, suggesting that naïve T cells primarily promote tumor growth. Adoptive transfer experiments demonstrated that naïve T cells are preferentially recruited from the blood into tumors with melanoma cell-derived CCL21-Ser expression. These results suggest that CCL21-Ser from melanoma cells promotes the infiltration of CCR7 + naïve T cells into the tumor tissues and creates a tumor microenvironment favorable for melanoma growth., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)