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It is well-known that the functioning of the immune system gradually deteriorates with age, and we are increasingly confronted with its consequences as the life expectancy of the human population increases. Changes in the T-cell pool are among the most prominent features of the changing immune system during healthy ageing, and changes in the naive T-cell pool in particular are generally held responsible for its gradual deterioration. These changes in the naive T-cell pool are thought to be due to involution of the thymus. It is commonly believed that the gradual loss of thymic output induces compensatory mechanisms to maintain the number of naive T cells at a relatively constant level, and induces a loss of diversity in the T-cell repertoire. Here we review the studies that support or challenge this widely-held view of immune ageing and discuss the implications for vaccination strategies., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This multiplex staining panel was developed to differentiate cattle T cells into conventional (CD4 and CD8) and unconventional (γδ-TCR) subsets as well as their stage of differentiation and activation. The combination of CD45RO and CD62L allows the identification of naïve (T Naïve ), central memory (T CM ), effector memory (T EM ) and terminal effector (T TE ) T cells. Activated cattle T cells (T AV ) can be identified by the cell surface expression of CD25. This panel was developed using cryopreserved cattle peripheral blood mononuclear cells (PBMCs) and tested on fresh as well as stimulated PBMCs. Therefore, this 8-color, 10-parameter flow cytometry panel simultaneously identifies cattle T Naïve , T AV , T CM , T EM , T TE and γδ-TCR cells. This panel will improve our ability to examine T-cell response to pathogens and vaccines in cattle including the potential to identify previously undescribed subpopulations. Furthermore, this panel can be readily optimized for other bovid species as many of these reagents are likely to cross react., (© 2023 The Authors. Cytometry Part A published by Wiley Periodicals LLC on behalf of International Society for Advancement of Cytometry.)

The specificity of T cells is that each T cell has only one T cell receptor (TCR). A T cell clone represents a collection of T cells with the same TCR sequence. Thus, the number of different T cell clones in an organism reflects the number of different T cell receptors (TCRs) that arise from recombination of the V(D)J gene segments during T cell development in the thymus. TCR diversity and more specifically, the clone abundance distribution, are important factors in immune functions. Specific recombination patterns occur more frequently than others while subsequent interactions between TCRs and self-antigens are known to trigger proliferation and sustain naive T cell survival. These processes are TCR-dependent, leading to clone-dependent thymic export and naive T cell proliferation rates. We describe the heterogeneous steady-state population of naive T cells (those that have not yet been antigenically triggered) by using a mean-field model of a regulated birth-death-immigration process. After accounting for random sampling, we investigate how TCR-dependent heterogeneities in immigration and proliferation rates affect the shape of clone abundance distributions (the number of different clones that are represented by a specific number of cells, or "clone counts"). By using reasonable physiological parameter values and fitting predicted clone counts to experimentally sampled clone abundances, we show that realistic levels of heterogeneity in immigration rates cause very little change to predicted clone-counts, but that modest heterogeneity in proliferation rates can generate the observed clone abundances. Our analysis provides constraints among physiological parameters that are necessary to yield predictions that qualitatively match the data. Assumptions of the model and potentially other important mechanistic factors are discussed., 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 © 2022 Dessalles, Pan, Xia, Maestrini, D’Orsogna and Chou.)

Adoptive cellular therapy using chimeric antigen receptors (CARs) has revolutionized our treatment of relapsed B cell malignancies and is currently being integrated into standard therapy. The impact of selecting specific T cell subsets for CAR transduction remains under investigation. Previous studies demonstrated that effector T cells derived from naive, rather than central memory T cells mediate more potent antitumor effects. Here, we investigate a method to skew CAR transduction toward naive T cells without physical cell sorting. Viral-mediated CAR transduction requires ex vivo T cell activation, traditionally achieved using antibody-mediated strategies. CD81 is a T cell costimulatory molecule that when combined with CD3 and CD28 enhances naive T cell activation. We interrogate the effect of CD81 costimulation on resultant CAR transduction. We identify that upon CD81-mediated activation, naive T cells lose their identifying surface phenotype and switch to a memory phenotype. By prelabeling naive T cells and tracking them through T cell activation and CAR transduction, we document that CD81 costimulation enhanced naive T cell activation and resultantly generated a CAR T cell product enriched with naive-derived CAR T cells., Competing Interests: The authors declare no competing interest., (Copyright © 2022 the Author(s). Published by PNAS.)

We studied the effects of pregnancy-specific β1-glycoprotein (PSG) on the replicative potential of naïve T cells (CD45RA + ) and immune memory T cells (CD45R0 + ) in vitro by evaluating the expression of the hTERT gene in combination with the proliferative activity of cells. Human PSG was obtained by the author's patented method of immunopurification using a biospecific sorbent with subsequent removal of immunoglobulin contamination on a HiTrap Protein G HP column. We used monocultures of CD45RA + and CD45R0 + lymphocytes isolated from peripheral blood mononuclear cells of reproductive-age women. It was found that PSG in physiological concentrations inhibited the expression of the hTERT gene mRNA in naïve T cells and immune memory T cells and simultaneously reduced the number of proliferating T cells estimated by the differential gating method. At the same time, PSG reduced CD71 expression only on naïve T cells without affecting this molecule on immune memory T cells. Thus, PSG decreased the replication potential and suppressed the proliferation of T cells and immune memory T cells, which in the context of pregnancy can contribute to the formation of immune tolerance to the semi-allogeneic embryo., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

Background & Aims: Little is known about the composition of intrahepatic immune cells and their contribution to the pathogenesis of primary sclerosing cholangitis (PSC). Herein, we aimed to create an atlas of intrahepatic T cells and thereby perform an in-depth characterization of T cells in inflamed human liver., Methods: Different single-cell RNA sequencing methods were combined with in silico analyses on intrahepatic and peripheral T cells from patients with PSC (n = 11) and healthy donors (HDs, n = 4). Multi-parameter flow cytometry and functional in vitro experiments were conducted on samples from patients with PSC (n = 24), controls with other liver diseases and HDs., Results: We identified a population of intrahepatic naive-like CD4 + T cells, which was present in all liver diseases tested, but particularly expanded in PSC. This population had a transcriptome and T cell receptor repertoire similar to circulating naive T cells but expressed a set of genes associated with tissue residency. Their periductal location supported the concept of tissue-resident naive-like T cells in livers of patients with PSC. Trajectory inference suggested that these cells had the developmental propensity to acquire a T helper 17 (T H 17) polarization state. Functional and chromatin accessibility experiments revealed that circulating naive T cells in patients with PSC were predisposed to polarize towards T H 17 cells., Conclusion: We report the first atlas of intrahepatic T cells in PSC, which led to the identification of a previously unrecognized population of tissue-resident naive-like T cells in the inflamed human liver and to the finding that naive CD4 + T cells in PSC harbour the propensity to develop into T H 17 cells., Lay Summary: The composition of intrahepatic immune cells in primary sclerosing cholangitis (PSC) and their contribution to disease pathogenesis is widely unknown. We analysed intrahepatic T cells and identified a previously uncharacterized population of liver-resident CD4 + T cells which are expanded in the livers of patients with PSC compared to healthy liver tissue and other liver diseases. These cells are likely to contribute to the pathogenesis of PSC and could be targeted in novel therapeutic approaches., Competing Interests: Conflict of interest The authors declare no conflict of interest. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Allergic reactions to drugs and chemicals are mediated by an adaptive immune response involving specific T cells. During thymic selection, T cells that have not yet encountered their cognate antigen are considered naive T cells. Due to the artificial nature of drug/chemical-T-cell epitopes, it is not clear whether thymic selection of drug/chemical-specific T cells is a common phenomenon or remains limited to few donors or simply does not exist, suggesting T-cell receptor (TCR) cross-reactivity with other antigens. Selection of drug/chemical-specific T cells could be a relatively rare event accounting for the low occurrence of drug allergy. On the other hand, a large T-cell repertoire found in multiple donors would underline the potential of a drug/chemical to be recognized by many donors. Recent observations raise the hypothesis that not only the drug/chemical, but also parts of the haptenated protein or peptides may constitute the important structural determinants for antigen recognition by the TCR. These observations may also suggest that in the case of drug/chemical allergy, the T-cell repertoire results from particular properties of certain TCR to recognize hapten-modified peptides without need for previous thymic selection. The aim of this review is to address the existence and the role of a naive T-cell repertoire in drug and chemical allergy. Understanding this role has the potential to reveal efficient strategies not only for allergy diagnosis but also for prediction of the immunogenic potential of new chemicals., 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 © 2021 Bechara, Feray and Pallardy.)

Whereas the human fetal immune system is poised to generate immune tolerance and suppress inflammation in utero, an adult-like immune system emerges to orchestrate anti-pathogen immune responses in post-natal life. It has been posited that cells of the adult immune system arise as a discrete ontological "layer" of hematopoietic stem-progenitor cells (HSPCs) and their progeny; evidence supporting this model in humans has, however, been inconclusive. Here, we combine bulk and single-cell transcriptional profiling of lymphoid cells, myeloid cells, and HSPCs from fetal, perinatal, and adult developmental stages to demonstrate that the fetal-to-adult transition occurs progressively along a continuum of maturity-with a substantial degree of inter-individual variation at the time of birth-rather than via a transition between discrete waves. These findings have important implications for the design of strategies for prophylaxis against infection in the newborn and for the use of umbilical cord blood (UCB) in the setting of transplantation., Competing Interests: Declaration of Interests C.J.Y. declares partnership at Related Sciences and TReX Bio and owns stock in DroPrint Genomics and Related Sciences. C.J.Y. is supported by research grants from CZ Biohub, CZI, and PICI., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Patients with end-stage renal disease (ESRD) exhibit a premature aging phenotype of immune system, which is recently concerned as a significant factor for increased risk of various morbidities. Nevertheless, there are few dates explicating the relevancy of T cell senescence to mortality. In this study, we prospectively studied the predictive value of T cell senescence for mortality in hemodialysis patients., Methods: Patients who had been on hemodialysis treatment for at least 6 months were enrolled. T cell senescence determined by differentiation status was evaluated by flow cytometry. Survival outcomes were estimated using the Kaplan-Meier method. Univariate and multivariate analyses were performed to evaluate the prognostic impact of T cell premature aging and other clinical factors on all-cause mortality., Results: A total of 466 patients (277 man and 169 women) were enrolled in this study. Decreased number of naïve T cell, as the most prominent feature of T cell senescence, did not change in parallel with age in these patients. Decreased absolute count of T cell, naïve T cell, CD4 + naïve T cell were independently associated with all-cause mortality. Decreased percentage of T cell and increased percentage of CD8 + central-memory T cell were also independently associated with all-cause mortality. After including all the T cell parameters in one regression model, only decreased count of naïve T cell was significantly associated with increased mortality in these patients., Conclusions: Aging-associated T cell changes are aggravated in ESRD patients. For the first time, our study demonstrates that naïve T cell depletion is a strong predictor of all-cause mortality in HD patients.

The survival of peripheral T cells is dependent on their access to peripheral LNs (pLNs) and stimulation by IL-7. In pLNs fibroblastic reticular cells (FRCs) and lymphatic endothelial cells (LECs) produce IL-7 suggesting their contribution to the IL-7-dependent survival of T cells. However, IL-7 production is detectable in multiple organs and is not restricted to pLNs. This raises the question whether pLN-derived IL-7 is required for the maintenance of peripheral T cell homeostasis. Here, we show that numbers of naive T cells (T N ) remain unaffected in pLNs and spleen of mice lacking Il7 gene activity in pLN FRCs, LECs, or both. In contrast, frequencies of central memory T cells (T CM ) are reduced in FRC-specific IL-7 KO mice. Thus, steady state IL-7 production by pLN FRCs is critical for the maintenance of T CM , but not T N , indicating that both T cell subsets colonize different ecological niches in vivo., (© 2020 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Echovirus 30 (E-30) is one of the most frequently isolated pathogens in aseptic meningitis worldwide. To gain access to the central nervous system (CNS), E-30 and immune cells have to cross one of the two main barriers of the CNS, the epithelial blood-cerebrospinal fluid barrier (BCSFB) or the endothelial blood-brain barrier (BBB). In an in vitro model of the BCSFB, it has been shown that E-30 can infect human immortalized brain choroid plexus papilloma (HIBCPP) cells., Methods: In this study we investigated the migration of different T cell subpopulations, naive and effector T cells, through HIBCPP cells during E-30 infection. Effects of E-30 infection and the migration process were evaluated via immunofluorescence and flow cytometry analysis, as well as transepithelial resistance and dextran flux measurement., Results: Th1 effector cells and enterovirus-specific effector T cells migrated through HIBCPP cells more efficiently than naive CD4 + T cells following E-30 infection of HIBCPP cells. Among the different naive T cell populations, CD8 + T cells crossed the E-30-infected HIBCPP cell layer in a significantly higher number than CD4 + T cells. A large amount of effector T cells also remained attached to the basolateral side of the HIBCPP cells compared with naive T cells. Analysis of HIBCPP barrier function showed significant alteration after E-30 infection and trans- as well as paracellular migration of T cells independent of the respective subpopulation. Morphologic analysis of migrating T cells revealed that a polarized phenotype was induced by the chemokine CXCL12, but reversed to a round phenotype after E-30 infection. Further characterization of migrating Th1 effector cells revealed a downregulation of surface adhesion proteins such as LFA-1 PSGL-1, CD44, and CD49d., Conclusion: Taken together these results suggest that naive CD8 + and Th1 effector cells are highly efficient to migrate through the BCSFB in an inflammatory environment. The T cell phenotype is modified during the migration process through HIBCPP cells.

Conventional dendritic cells (cDCs) cannot be infected by porcine reproductive and respiratory syndrome virus (PRRSV) but respond to infection via cytokine production, indicating a possible role in initiation/regulation of the immune response against PRRSV. In this work, we evaluated the responses of splenic and blood cDCs, with DEC205 + CADM1 + CD172a +/- phenotype, as well as those of CD163 + cells against PRRSV and porcine epidemic diarrhea virus (PEDV). Both populations were incubated in the presence of PRRSV or PEDV with and without naïve CD3 + T cells, and cytokine responses were evaluated by qPCR and ELISA. Our results showed that cDCs, but not CD163 + cells, produced IL-12 in response to PRRSV. PEDV did not induce IL-12 production. Cocultures of cDCs and autologous naïve CD3 + cells resulted in decreased IL-12 production and low expression of IFN-γ transcripts in response to PRRSV. Interestingly, cDCs increased the proliferation of naïve T cells in the presence of PRRSV compared with that achieved with monocytes and peripheral blood mononuclear cells (PBMCs). Cocultures of CD163 + cells induced IL-10 and IL-4 expression in the presence of PRRSV and PEDV, respectively. In conclusion, cDCs can selectively produce IL-12 in response to PRRSV but poorly participate in the activation of naïve T cells.

We studied the role of native α-fetoprotein preparation in the regulation of proliferation and functional activity of naïve T cells and immune memory T cells in vitro. The study was carried out on separated fractions of naïve T cells (CD45RA + ) and immune memory T cells (CD45R0 + ) incubated with α-fetoprotein under conditions of TCR activation. At the level of naïve T cells, α-fetoprotein in a concentration of 100 U/ml reduced the expression of CD28, but increased the expression of CD25, while at the level of immune memory T cells α-fetoprotein (50 and 100 U/ml) only suppressed the expression of CD25. No effects of α-fetoprotein on the proliferative status of the studied lymphocyte subpopulations and on the expression of CD71 (proliferation marker) by these cells were detected. Addition of α-fetoprotein in a concentration of 100 U/ml increased the level of IL-2 in naïve T cell culture supernatants, while production of IL-2 by memory T cells remained unchanged. These data demonstrated the priority aspects of regulation of the functional activities of naïve T cells and immune memory T cells.

Mammalian STE20-like protein kinase 1/2 (MST1/2) and nuclear Dbf2-related kinase 1/2 (NDR1/2) are core components of Hippo signaling that are also known to be important regulators of lymphocyte trafficking. However, little is understood about the roles of other Hippo pathway molecules in these cells. Here, we present the first analysis of the function of Mps one binder kinase activator-1 (MOB1) in T lymphocytes in vivo. T-cell-specific double knockout (DKO) of MOB1A/B in mice [tMob1 DKO mice] reduces the number of naïve T cells in both the circulation and secondary lymphoid organs, but leads to an accumulation of CD4 + CD8 - and CD4 - CD8 + single-positive (SP) cells in the thymus. In vitro, naïve MOB1A/B-deficient T cells show increased apoptosis and display impaired trafficking capacity in response to the chemokine CCL19. These defects are linked to suppression of the activation of MST and NDR kinases, but are independent of the downstream transcriptional co-activator Yes-associated protein 1 (YAP1). Thus, MOB1 proteins play an important role in thymic egress and T-cell survival that is mediated by a pathway other than conventional Hippo-YAP1 signaling., (© 2019 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.)

Unique molecular identifiers (MIDs) have been demonstrated to effectively improve immune repertoire sequencing (IR-seq) accuracy, especially to identify somatic hypermutations in antibody repertoire sequencing. However, evaluating the sensitivity to detect rare T cells and the degree of clonal expansion in IR-seq has been difficult due to the lack of knowledge of T cell receptor (TCR) RNA molecule copy number and a generalized approach to estimate T cell clone size from TCR RNA molecule quantification. This limited the application of TCR repertoire sequencing (TCR-seq) in clinical settings, such as detecting minimal residual disease in lymphoid malignancies after treatment, evaluating effectiveness of vaccination and assessing degree of infection. Here, we describe using an MID Clustering-based IR-Seq (MIDCIRS) method to quantitatively study TCR RNA molecule copy number and clonality in T cells. First, we demonstrated the necessity of performing MID sub-clustering to eliminate erroneous sequences. Further, we showed that MIDCIRS enables a sensitive detection of a single cell in as many as one million naïve T cells and an accurate estimation of the degree of T cell clonal expression. The demonstrated accuracy, sensitivity, and wide dynamic range of MIDCIRS TCR-seq provide foundations for future applications in both basic research and clinical settings.

Assessment of thymic output by measurement of naive T cells is carried out routinely in clinical diagnostic laboratories, predominantly using flow cytometry with a suitable panel of antibodies. Naive T cell measurements can also be made using molecular analyses to quantify T cell receptor excision circle (TRECs) levels in sorted cells from peripheral blood. In this study we have compared TRECs levels retrospectively with CD45RA + CD27 + T cells and also with CD45RA + CD31 + T cells in 134 patient samples at diagnosis or during follow-up. Both panels provide naive T cell measurements that have a strongly positive correlation with TRECs numbers and are suitable for use with enumerating naive T cell levels in a clinical laboratory., (© 2017 British Society for Immunology.)

The role of human chorionic gonadotropin (hCG) in the regulation of molecular genetics factors determining the functional activity of human naïve and memory T cells in vitro was studied. It was found that hCG (10 and 100IU/ml) inhibited CD28 and CD25 expression on the naïve T cells (CD45RA+) and CD25 expression on the memory T cells (CD45R0+). hCG didn't affect the CD71 proliferation marker expression in total. Nevertheless, hCG reduced the percentage of proliferating memory T cells with simultaneous suppression of CD71 expression on proliferating CD45R0+cells. In parallel, expression of U2af1l4, Gfi1, and hnRNPLL genes, which are Ptprc gene alternative splicing regulators was evaluated. It was established that hCG stimulated the expression of U2af1l4 and hnRNPLL genes, responsible for the assembly of CD45R0 in memory T cells, but reduced the expression of Gfi1 in these cells. In general, hCG promotes the differentiation of memory T cells by increasing of CD45R0 expression, but inhibits proliferation and CD25 expression which reflects their functional activity., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The effects of chorionic gonadotropin (hCG) on the expression of the hTERT gene in combination with the conversion of the phenotype of naive T-cells and T-cells of immune memory in vitro were studied. hCG inhibited expression of hTERT mRNA in naive T-cells (CD45RA+) and immune memory T cells (CD45RO+), causing a decrease in the replicative potential of the cells. The presence of hCG in the culture led to the conversion of the phenotype of T-lymphocytes. hCG reduced the number of proliferating T-cells of immune memory, estimated by phenotypic signs by differential gating. hCG (10 IU/ml and 100 IU/ml) inhibited expression of CD25 by the studied populations, but did not modulate expression of the CD71 proliferation marker. Thus, hCG inhibited the functional activity of naive T-cells and T-cells of immune memory, which, in the context of pregnancy, can contribute to the formation of immune tolerance to the semi-allogenic fetus.

Intensified efforts to promote protective T cell-based immunity in vaccines and immunotherapies have created a compelling need to expand our understanding of human T cell function and maintenance beyond its characterization in peripheral blood. Mouse studies of T cell immunity show that, in response to infection, T cells migrate to diverse sites and persist as tissue-resident memory T cells (TRM), which mediate rapid in situ protection on antigen recall. Here we discuss new approaches to probe human T cell immunity, including novel sampling, that indicate a broad distribution and high frequency of human TRM in multiple sites. These newer findings further implicate anatomic compartmentalization as a generalized mechanism for long-term maintenance of human T cells throughout life., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

This study compares the human immune systems of neonates and adults. Flow cytometric analysis was used to study the cellular phenotypes of cord blood (CB) and adult peripheral blood (APB). Luminex analysis was used to determine the levels of cytokines in cell culture supernatants. Our findings indicate that T cells in CB were mainly naïve and thus less responsive to PMA/ionomycin with the synthesis of cytokines. The percentages of CD3(+)CD4(+)CD25(high) and of CD3(+)CD4(+)CD25(dim) cells expressing chemokine receptors were different between CB and APB. TLR1, TLR6 and TLR9 expressions on NK and NKT cells also differed between CB and APB. CB monocyte-derived macrophages responded better than APB macrophages to TLR ligands with increased secretion of inflammatory cytokines, especially IL-6. The high levels of the inflammatory cytokines in cell culture supernatants of CB were mainly due to higher numbers of responsive macrophages, since dendritic cell numbers were lower in CB than APB., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

When encountering foreign antigens, naïve T cells become activated and differentiate into effector and memory T cells. They represent therefore the primary source to mount an immune response against pathogens or tumors. Recent evidence of both quantitative and qualitative alterations of naïve T cells has accumulated in aged mice, indicating that the successful generation of primary T cell responses from the naïve T cell pool may be compromised with old age. However, the vast majority of the data supporting compromised naïve T cell priming efficacy with old age have been produced in animal models, and the situation is much less clear in humans. In the elderly, the involution of the thymus and the associated decline in thymic output result in a decreased number of naïve T cells, which is partially compensated by homeostatic proliferation. Emerging evidence suggest that alterations of the TCR repertoire diversity and intrinsic defects of old CD4(+) naïve T cells may impact on their responsiveness to antigenic stimulation. Increasing focus on the study of naïve T cells (in particular CD8(+)) in old humans are needed to fill the gaps in our understanding of reduced cellular immunity with aging., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Graft-versus-host disease (GVHD) is a frequent major complication of allogeneic hematopoietic cell transplantation (HCT). Approaches that selectively deplete T cells that cause GVHD from allogeneic stem cell grafts and preserve T cells specific for pathogens may improve HCT outcomes. It has been hypothesized that the majority of T cells that can cause GVHD reside within the naïve T cell (TN) subset, and previous studies performed in mouse models and with human cells in vitro support this hypothesis. As a prelude to translating these findings to the clinic, we developed and evaluated a novel 2-step clinically compliant procedure for manipulating peripheral blood stem cells (PBSC) to remove TN, preserve CD34(+) hematopoietic stem cells, and provide for a fixed dose of memory T cells (TM) that includes T cells with specificity for common opportunistic pathogens encountered after HCT. Our studies demonstrate effective and reproducible performance of the immunomagnetic cell selection procedure for depleting TN. Moreover, after cell processing, the CD45RA-depleted PBSC products are enriched for CD4(+) and CD8(+) TM with a central memory phenotype and contain TM cells that are capable of proliferating and producing effector cytokines in response to opportunistic pathogens., (Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

The specificity of T cells is that each T cell has only one T cell receptor (TCR). A T cell clone represents a collection of T cells with the same TCR sequence. Thus, the number of different T cell clones in an organism reflects the number of different T cell receptors (TCRs) that arise from recombination of the V(D)J gene segments during T cell development in the thymus. TCR diversity and more specifically, the clone abundance distribution, are important factors in immune functions. Specific recombination patterns occur more frequently than others while subsequent interactions between TCRs and self-antigens are known to trigger proliferation and sustain naive T cell survival. These processes are TCR-dependent, leading to clone-dependent thymic export and naive T cell proliferation rates. We describe the heterogeneous steady-state population of naive T cells (those that have not yet been antigenically triggered) by using a mean-field model of a regulated birth-death-immigration process. After accounting for random sampling, we investigate how TCR-dependent heterogeneities in immigration and proliferation rates affect the shape of clone abundance distributions (the number of different clones that are represented by a specific number of cells, or clone counts). By using reasonable physiological parameter values and fitting predicted clone counts to experimentally sampled clone abundances, we show that realistic levels of heterogeneity in immigration rates cause very little change to predicted clone-counts, but that modest heterogeneity in proliferation rates can generate the observed clone abundances. Our analysis provides constraints among physiological parameters that are necessary to yield predictions that qualitatively match the data. Assumptions of the model and potentially other important mechanistic factors are discussed.

Background: The HIV co-receptors CXCR4 and CCR5 play an important role in HIV infection and replication. Therefore we hypothesize that long-term non-progressors (LTNP) with viral control have lower expression of CCR5 and CXCR4 on CD4+ cells, specifically on memory T-lymphocytes since they are the primary target cells of HIV. Methods: In this cross-sectional study, we included five HIV-infected LTNP with viral control (CD4 > 750cell/µl & HIV < 50 copies for =2 years), thirteen HIV-infected and seven HIV-uninfected individuals at Radboud UMC Nijmegen, the Netherlands. We determined the CCR5 and CXCR4 expression among CD4+ and CD8+ lymphocyte subsets; memory (CD45RO+), naïve (CD45RA+) cells and regulatory T-cells (CD4+CD25highFoxP3+). In addition, CCR5Δ32 polymorphism is related with disease progression and was therefore determined using polymerase chain reaction. Results: The percentage of CCR5-expressing CD4+ cells of LTNP was comparable with healthy controls; whereas HIV-infected individuals showed more CCR5-expressing cells. This was observed in memory and naïve CD4+ cells, but not in regulatory T-cells. The mean fluorescence intensity of CCR5-expressing CD4+ cells was similar in all groups. All groups had comparable percentages of CXCR4-expressing cells. The mean fluorescence intensity of CXCR4-expressing cells was significantly higher in HIV-infected normally progressors in both memory and naïve CD4+ cells, but not in CD8+ cells. The CCR5Δ32 polymorphism was not related to group. Conclusions: We show that HIV affects -directly or indirectly-the expression of CCR5 in CD4+ Tlymphocytes; yet this effect is not seen in LTNP with viral control. Avoiding upregulation of CCR5 could be an important method via which LTNP counteracts the effects of HIV and suppresses viral replication. Exploring how LTNP suppress the upregulation of CCR5 could be an important step for discovering new therapeutics. [ABSTRACT FROM AUTHOR]