B cell abnormalities and autoantibody production in patients with partial RAG deficiency.

Mutations in the recombination activating gene 1 (RAG1) and RAG2 in humans are associated with a broad spectrum of clinical phenotypes, from severe combined immunodeficiency to immune dysregulation. Partial (hypomorphic) RAG deficiency (pRD) in particular, frequently leads to hyperinflammation and autoimmunity, with several underlying intrinsic and extrinsic mechanisms causing a break in tolerance centrally and peripherally during T and B cell development. However, the relative contributions of these processes to immune dysregulation remain unclear. In this review, we specifically focus on the recently described tolerance break and B cell abnormalities, as well as consequent molecular and cellular mechanisms of autoantibody production in patients with pRD.

Hypoxia induces dichotomous and reversible attenuation of T cell responses through reactive oxygen species-dependent phenotype redistribution and delay in lymphoblast proliferation.

As T cells transit between blood, lymphoid organs, and peripheral tissues, they experience varied levels of oxygen/hypoxia in inflamed tissues, skin, intestinal lining, and secondary lymphoid organs. Critical illness among COVID-19 patients is also associated with transient hypoxia and attenuation of T cell responses. Hypoxia is the fulcrum of altered metabolism, impaired functions, and cessation of growth of a subset of T cells. However, the restoration of normal T cell functions following transient hypoxia and kinetics of their phenotype-redistribution is not completely understood. Here, we sought to understand kinetics and reversibility of dichotomous T cell responses under sustained and transient hypoxia. We found that a subset of activated T cells accumulated as lymphoblasts under hypoxia. Further, T cells showed the normal expression of activation markers CD25 and CD69 and inflammatory cytokine secretion but a subset exhibited delayed cell proliferation under hypoxia. Increased levels of reactive oxygen species (ROS) in cytosol and mitochondria were seen during dichotomous and reversible attenuation of T cell response under hypoxia. Cell cycle analysis revealed maximum levels of cytosolic and mitochondrial ROS in dividing T cells (in S, G2, or M phase). Hypoxic T cells also showed specific attenuation of activation induced memory phenotype conversion without affecting naïve and activated T cells. Hypoxia-related attenuation of T cell proliferation was also found to be reversible in an allogeneic leukocyte specific mixed lymphocyte reaction assay. In summary, our results show that hypoxia induces a reversible delay in proliferation of a subset of T cells which is associated with obliteration of memory phenotype and specific increase in cytosolic/mitochondrial ROS levels in actively dividing subpopulation. Thus, the transient reoxygenation of hypoxic patients may restore normal T cell responses.

Progress of T lymphocytes in the pathogenesis of bronchopulmonary dysplasia in premature infants / 国际儿科学杂志

Bronchopulmonary dysplasia(BPD)is a severe complication in premature infants, and the pathogenesis remains complex, potentially involving pulmonary inflammatory injury and faulty reparative response.T-cell immaturity in preterm neonates and the upregulation of related harmful regulatory genes, as well as the imbalance of T-cell homeostasis, have been reported to contribute significantly to the development of inflammatory diseases.Growing evidence suggests that alterations in the levels and functions of T cell subsets may participate in the development of BPD, serving as a new avenue for BPD prevention and treatment.Herein, we summarize recent advancements in understanding the role of T lymphocytes in the pathogenesis of BPD.

Analysis of HIV latent infection model with multiple infection stages and different drug classes.

Latently infected CD4+ T cells represent one of the major obstacles to HIV eradication even after receiving prolonged highly active anti-retroviral therapy (HAART). Long-term use of HAART causes the emergence of drug-resistant virus which is then involved in HIV transmission. In this paper, we develop mathematical HIV models with staged disease progression by incorporating entry inhibitor and latently infected cells. We find that entry inhibitor has the same effect as protease inhibitor on the model dynamics and therefore would benefit HIV patients who developed resistance to many of current anti-HIV medications. Numerical simulations illustrate the theoretical results and show that the virus and latently infected cells reach an infected steady state in the absence of treatment and are eliminated under treatment whereas the model including homeostatic proliferation of latently infected cells maintains the virus at low level during suppressive treatment. Therefore, complete cure of HIV needs complete eradication of latent reservoirs.

Lymphopenia and Mechanisms of T-Cell Regeneration.

Chronic lymphopenia, in particular, T-lymphocyte deficiency, increases the risk of death from cancer, cardiovascular and respiratory diseases and serves as a risk factor for a severe course and poor outcome of infectious diseases such as COVID-19. The regeneration of T-lymphocytes is a complex multilevel process, many questions of which still remain unanswered. The present review considers two main pathways of increasing the T-cell number in lymphopenia: production in the thymus and homeostatic proliferation in the periphery. Literature data on the signals that regulate each pathway are summarized. Their contribution to the quantitative and qualitative restoration of the immune cell pool is analyzed. The features of CD4+ and CD8+ T-lymphocytes' regeneration are considered.

T Cell Homeostatic Proliferation Promotes a Redox State That Drives Metabolic and Epigenetic Upregulation of Inflammatory Pathways in Lupus.

Significance: Numerous abnormalities in T cells have been described in patients with systemic lupus erythematosus (SLE), including lymphopenia, DNA demethylation, expression of endogenous retroviruses (ERVs), increased cell death, enlarged mitochondria, production of reactive oxygen species (ROS), and the appearance of unusual CD4-CD8- T cells. Our studies propose a model in which accelerated homeostatic proliferation of T cells promotes an epigenetic and metabolic program, leading to this cluster of abnormalities. Recent Advances: Growing knowledge of the innate immune disorders in SLE has included increased mitochondrial size and ROS production that induces oligomerization of the mitochondrial antiviral signaling (MAVS) protein and type I interferon production, as well as DNA demethylation, upregulation of inflammatory genes, and expression of certain ERVs in SLE peripheral blood mononuclear cells. All these events are part of the cellular program that occurs during homeostatic proliferation of T cells. Evidence from a murine model of SLE as well as in human SLE reveals that increased T cell homeostatic proliferation may be a driving factor in these processes. Critical Issues: Despite extensive knowledge of the myriad autoantibodies in SLE and other immune abnormalities, a cogent model has been lacking to link the numerous and seemingly disparate immune aberrations. This may partly explain the general lack of new drugs specifically for SLE in over 50 years. A more coherent model of SLE would not only unify the variety of immune abnormalities is SLE but would also suggest new therapies. Future Directions: The model of augmented homeostatic proliferation leading to increased mitochondrial mass, ROS, DNA demethylation, and upregulation of inflammatory genes suggests strategic new targets for SLE, including antioxidants and certain inhibitors of metabolism. Antioxid. Redox Signal. 36, 410-422.

Distinct immune trajectories in patients with chromosome 22q11.2 deletion syndrome and immune-mediated diseases.

BACKGROUND: Identification of biomarkers associated with immune-mediated diseases in 22q11.2 deletion syndrome is an evolving field. OBJECTIVES: We sought to use a carefully phenotyped cohort to study immune parameters associated with autoimmunity and atopy in 22q11.2 deletion syndrome to define biomarkers associated with immune-mediated disease in this syndrome. METHODS: Chart review validated autoimmune disease and atopic condition diagnoses. Laboratory data were extracted for each subcohort and plotted according to age. A random-effects model was used to define statistical significance. RESULTS: CD19, CD4, and CD4/45RA lymphocyte populations were not different from the general cohort for patients with atopic conditions. CD4/45RA T cells were significantly lower in the subjects with immune thrombocytopenia compared with the general cohort, and CD4 T-cell counts were lower in patients with autoimmune thyroid disease. CONCLUSIONS: The mechanisms of autoimmunity in cytopenias may be distinct from those of solid-organ autoimmunity in 22q11.2 deletion syndrome. This study identifies potential biomarkers for risk stratification among commonly obtained laboratory studies.

Pharmacologic control of homeostatic and antigen-driven proliferation to target HIV-1 persistence.

The presence of latent human immunodeficiency virus 1 (HIV-1) in quiescent memory CD4 + T cells represents a major barrier to viral eradication. Proliferation of memory CD4 + T cells is the primary mechanism that leads to persistence of the latent reservoir, despite effective antiretroviral therapy (ART). Memory CD4 + T cells are long-lived and can proliferate through two mechanisms: homeostatic proliferation via γc-cytokine stimulation or antigen-driven proliferation. Therefore, therapeutic modalities that perturb homeostatic and antigen-driven proliferation, combined with ART, represent promising strategies to reduce the latent reservoir. In this study, we investigated a library of FDA-approved oncology drugs to determine their ability to inhibit homeostatic and/or antigen-driven proliferation. We confirmed potential hits by evaluating their effects on proliferation in memory CD4 + T cells from people living with HIV-1 on ART (PLWH) and interrogated downstream signaling of γc-cytokine stimulation. We found that dasatinib and ponatinib, tyrosine kinase inhibitors, and trametinib, a MEK inhibitor, reduced both homeostatic and antigen-driven proliferationby >65%, with a reduction in viability <45%, ex vivo. In memory CD4 + T cells from PLWH, only dasatinib restricted both homeostatic and antigen-driven proliferation and prevented spontaneous rebound, consistent with promoting a smaller reservoir size. We show that dasatinib restricts IL-7 induced proliferation through STAT5 phosphorylation inhibition. Our results establish that the anti-cancer agent dasatinib is an exciting candidate to be used as an anti-proliferative drug in a clinical trial, since it efficiently blocks proliferation and iswell tolerated in patients with chronic myeloid leukemia (CML).

Sepsis leads to lasting changes in phenotype and function of memory CD8 T cells.

The global health burden due to sepsis and the associated cytokine storm is substantial. While early intervention has improved survival during the cytokine storm, those that survive can enter a state of chronic immunoparalysis defined by transient lymphopenia and functional deficits of surviving cells. Memory CD8 T cells provide rapid cytolysis and cytokine production following re-encounter with their cognate antigen to promote long-term immunity, and CD8 T cell impairment due to sepsis can pre-dispose individuals to re-infection. While the acute influence of sepsis on memory CD8 T cells has been characterized, if and to what extent pre-existing memory CD8 T cells recover remains unknown. Here, we observed that central memory CD8 T cells (TCM) from septic patients proliferate more than those from healthy individuals. Utilizing LCMV immune mice and a CLP model to induce sepsis, we demonstrated that TCM proliferation is associated with numerical recovery of pathogen-specific memory CD8 T cells following sepsis-induced lymphopenia. This increased proliferation leads to changes in composition of memory CD8 T cell compartment and altered tissue localization. Further, memory CD8 T cells from sepsis survivors have an altered transcriptional profile and chromatin accessibility indicating long-lasting T cell intrinsic changes. The sepsis-induced changes in the composition of the memory CD8 T cell pool and transcriptional landscape culminated in altered T cell function and reduced capacity to control L. monocytogenes infection. Thus, sepsis leads to long-term alterations in memory CD8 T cell phenotype, protective function and localization potentially changing host capacity to respond to re-infection.

A dirty cut, a nasty burn, a severe COVID infection; there are many ways for someone to develop sepsis. This life-threatening condition emerges when the immune system overreacts to a threat and ends up damaging the body. Even when patients survive, they are often left with a partially impaired immune system that cannot adequately protect against microbes and cancer; this is known as immunoparalysis. Memory CD8 T cells, a type of immune cell that is compromised by sepsis, are a long-lived population of cells that 'remember' previous infection or vaccination, and then react faster to prevent the same illness if the person ever encounters the same threat again. Yet it is unclear how exactly sepsis harms the function and representation of memory CD8 T cells, and the immune system in general. Jensen et al. investigated this question, first by showing that sepsis leads to a profound loss of memory CD8 T cells, but that surviving memory CD8 T cells multiply quickly ­ especially a subpopulation known as central memory CD8 T cells ­ to re-establish the memory CD8 T cell population. Since the central memory CD8 T cells proliferate better than the other memory T cells this alters the overall composition of the pool of memory CD8 T cells, with central memory cells becoming overrepresented. Further experiments revealed that this biasing toward central memory T cells, due to sepsis, created long-term changes in the distribution of memory CD8 T cells throughout the body. The way the genetic information of these cells was packaged had also been altered, as well as which genes were switched on or off. Overall, these changes reduced the ability of memory CD8 T cells to control infections. Together, these findings help to understand how immunoparalysis can emerge after sepsis, and what could be done to correct it. These findings could also be applied to other conditions ­ such as COVID-19 ­ which may cause similar long-term changes to the immune system.

Functional roles of graft-infiltrating lymphocytes during early-phase post-transplantation in mouse cardiac transplantation models.

Immunological behavior of graft-infiltrating lymphocytes (GILs) determines the graft fate (i.e., rejection or acceptance). Nevertheless, the functional alloreactivity and the phenotype of GILs at various times during the early post-transplantation phase have not been fully elucidated. We examined the immunological activities of early-phase GILs using a murine model of cardiac transplantation. GILs from 120-h allografts, but not 72-h allografts, showed robust activation and produced proinflammatory cytokines. In particular, a significant increase in CD69+ T-bet+ Nur77+ T cells was detected in 120-h allografts. Furthermore, isolated GILs were used to reconstitute BALB/c Rag2-/- γc-/- (BRG) mice. BRG mice reconstituted with 120-h GILs displayed donor-specific immune reactivity and rejected donor strain cardiac allografts; conversely, 72-h GILs exhibited weak anti-donor reactivity and did not reject allografts. These findings were confirmed by re-transplantation of cardiac allografts into BRG mice at 72-h post-transplantation. Re-transplanted allografts continued to function for >100 days, despite the presence of CD3+ GILs. In conclusion, the immunological behavior of GILs considerably differs over time during the early post-transplantation phase. A better understanding of the functional role of early-phase GILs may clarify the fate determination process in the graft-site microenvironment.

Highly proliferative and functional PD-1+ and TIM-3+ T cells are transiently increased in multiple myeloma following autologous hematopoietic stem cell transplantation.

The aim of our prospective study was to assess recovery dynamics and functional characteristics of PD-1+ and TIM-3+ T cells in multiple myeloma (MM) patients following high-dose chemotherapy (HDCT) with autologous hematopoietic stem cell transplantation (AHSCT). Peripheral blood, autograft and bone marrow samples were obtained from 46 MM patients before conditioning, at the engraftment, following six and 12 months post-transplant. Frequencies of CD4+ and CD8+ T cells expressing PD-1 and TIM-3 and intracellular expression of Ki-67 and Granzyme B were evaluated. Counts of PD-1+ and TIM-3+ T cells at the engraftment were significantly higher comparing with the levels before HDCT and 6-12 months following AHSCT. The post-transplant increase in the studied subsets was due to a temporary enhancement in proliferation activity. The cytotoxic potential of PD-1- and TIM-3-expressing CD8+ T cells was higher at the engraftment comparing with the pre-transplant and remained at the same level for at least 12 months. The increase in CD4+PD-1+ and CD8+TIM-3+ T cells at the engraftment was associated with higher absolute counts of their reinfused counterparts. Circulating PD-1+ CD8+ and TIM-3+ CD4+ T cells were increased in patients after post-transplant relapse comparing with the ones in remission. Homeostatic proliferation plays a key role in the upregulation of inhibitory checkpoint receptors on functional T cells under lymphopenic conditions. In this regard, it is difficult to predict both the efficacy and adverse reactions of therapy with checkpoint inhibitors on the course of MM after HDCT with AHSCT. Précis. Homeostatic proliferation plays apparently a key role in the upregulation of PD-1 and TIM-3 on functional T cells after AHSCT and appears to be a normal physiological process, contrary to relapse-associated increase in PD-1+ and TIM-3+ T cells.

Immune Equilibrium Depends on the Interaction Between Recognition and Presentation Landscapes.

In this review, we described the structure and organization of antigen-recognizing repertoires of B and T cells from the standpoint of modern immunology. We summarized the latest advances in bioinformatics analysis of sequencing data from T and B cell repertoires and also presented contemporary ideas about the mechanisms of clonal diversity formation at different stages of organism development. At the same time, we focused on the importance of the allelic variants of the HLA genes and spectra of presented antigens for the formation of T-cell receptors (TCR) landscapes. The main idea of this review is that immune equilibrium and proper functioning of immunity are highly dependent on the interaction between the recognition and the presentation landscapes of antigens. Certain changes in these landscapes can occur during life, which can affect the protective function of adaptive immunity. We described some mechanisms associated with these changes, for example, the conversion of effector cells into regulatory cells and vice versa due to the trans-differentiation or bystander effect, changes in the clonal organization of the general TCR repertoire due to homeostatic proliferation or aging, and the background for the altered presentation of some antigens due to SNP mutations of MHC, or the alteration of the presenting antigens due to post-translational modifications. The authors suggest that such alterations can lead to an increase in the risk of the development of oncological and autoimmune diseases and influence the sensitivity of the organism to different infectious agents.

Chromatin Modifications in 22q11.2 Deletion Syndrome.

PURPOSE: Chromosome 22q11.2 deletion syndrome is a common inborn error of immunity. The early consequences of thymic hypoplasia are low T cell numbers. Later in life, atopy, autoimmunity, inflammation, and evolving hypogammaglobulinemia can occur and the causes of these features are not understood. This study utilized an unbiased discovery approach to define alterations in histone modifications. Our goal was to identify durable chromatin changes that could influence cell behavior. METHODS: CD4 T cells and CD19 B cells underwent ChIP-seq analysis using antibodies to H3K4me3, H3K27ac, and H4ac. RNA effects were defined in CD4 T cells by RNA-seq. Serum cytokines were examined by Luminex. RESULTS: Histone marks of transcriptional activation at CD4 T cell promoters and enhancers were globally increased. The promoter activation signature had elements related to T cell activation and inflammation, concordant with effects seen in the transcriptome. B cells, in contrast, had a minimally altered epigenetic landscape in 22q11.2. Both cell types had an "edge" effect with markedly altered chromatin adjacent to the deletion. CONCLUSIONS: People with 22q11.2 deletion have altered CD4 T cell chromatin and a transcriptome concordant with the changes in the epigenome. These effects support a disease model where qualitative changes to T cells occur in addition to quantitative defects that have been well characterized. This study offers unique insight into qualitative differences in the T cells in 22q11.2 deletion, an aspect that has received limited attention.

Suppression of the Immune Response by Syngeneic Splenocytes Adoptively Transferred to Sublethally Irradiated Mice.

The peripheral T-cell pool consists of several, functionally distinct populations of CD8+ T cells. CD44 and CD62L are among the major surface markers that allow us to define T-cell populations. The expression of these molecules depends on the functional status of a T lymphocyte. Under lymphopenic conditions, peripheral T cells undergo homeostatic proliferation and acquire the memory-like surface phenotype CD44hiCD62Lhi. However, the data on the functional activity of these cells remains controversial. In this paper, we analyzed the effects of the adoptive transfer of syngeneic splenocytes on the recovery of CD8+ T cells in sublethally irradiated mice. Our data demonstrate that under lymphopenia, donor lymphocytes form a population of memory-like CD8+ T cells with the phenotype CD122+CD5+CD49dhiCXCR3+ that shares the phenotypic characteristics of true memory cells and suppressive CD8+ T cells. Ex vivo experiments showed that after adoptive transfer in irradiated mice, T cells lacked the functions of true effector or memory cells; the allogeneic immune response and immune response to pathogens were greatly suppressed in these mice.

Regulatory T Cells Fail to Suppress Fast Homeostatic Proliferation In Vitro.

Homeostatic proliferation (HP) is a physiological process that reconstitutes the T cell pool after lymphopenia involving Interleukin-7 and 15 (IL-7 and IL-15), which are the key cytokines regulating the process. However, there is no evidence that these cytokines influence the function of regulatory T cells (Tregs). Since lymphopenia often accompanies autoimmune diseases, we decided to study the functional activity of Tregs stimulated by HP cytokines from patients with rheumatoid arthritis as compared with that of those from healthy donors. Since T cell receptor (TCR) signal strength determines the intensity of HP, we imitated slow HP using IL-7 or IL-15 and fast HP using a combination of IL-7 or IL-15 with anti-CD3 antibodies, cultivating Treg cells with peripheral blood mononuclear cells (PBMCs) at a 1:1 ratio. We used peripheral blood from 14 patients with rheumatoid arthritis and 18 healthy volunteers. We also used anti-CD3 and anti-CD3 + IL-2 stimulation as controls. The suppressive activity of Treg cells was evaluated in each case by the inhibition of the proliferation of CD4+ and CD8+ cells. The phenotype and proliferation of purified CD3+CD4+CD25+CD127lo cells were assessed by flow cytometry. The suppressive activity of the total pool of Tregs did not differ between the rheumatoid arthritis and healthy donors; however, it significantly decreased in conditions close to fast HP when the influence of HP cytokines was accompanied by anti-CD3 stimulation. The Treg proliferation caused by HP cytokines was lower in the rheumatoid arthritis (RA) patients than in the healthy individuals. The revealed decrease in Treg suppressive activity could impact the TCR landscape during lymphopenia and lead to the proliferation of potentially self-reactive T cell clones that are able to receive relatively strong TCR signals. This may be another explanation as to why lymphopenia is associated with the development of autoimmune diseases. The revealed decrease in Treg proliferation under IL-7 and IL-15 exposure can lead to a delay in Treg pool reconstitution in patients with rheumatoid arthritis in the case of lymphopenia.

SARS-CoV-2-Specific T Cells Exhibit Phenotypic Features of Helper Function, Lack of Terminal Differentiation, and High Proliferation Potential.

Convalescing coronavirus disease 2019 (COVID-19) patients mount robust T cell responses against SARS-CoV-2, suggesting an important role of T cells in viral clearance. To date, the phenotypes of SARS-CoV-2-specific T cells remain poorly defined. Using 38-parameter CyTOF, we phenotyped longitudinal specimens of SARS-CoV-2-specific CD4+ and CD8+ T cells from nine individuals who recovered from mild COVID-19. SARS-CoV-2-specific CD4+ T cells were exclusively Th1 cells and predominantly Tcm cells with phenotypic features of robust helper function. SARS-CoV-2-specific CD8+ T cells were predominantly Temra cells in a state of less terminal differentiation than most Temra cells. Subsets of SARS-CoV-2-specific T cells express CD127, can proliferate homeostatically, and can persist for over 2 months. Our results suggest that long-lived and robust T cell immunity is generated following natural SARS-CoV-2 infection and support an important role of SARS-CoV-2-specific T cells in host control of COVID-19.

The Role of TNFR2 and DR3 in the In Vivo Expansion of Tregs in T Cell Depleting Transplantation Regimens.

Regulatory T cells (Tregs) are essential for the maintenance of tolerance to self and non-self through cell-intrinsic and cell-extrinsic mechanisms. Peripheral Tregs survival and clonal expansion largely depend on IL-2 and access to co-stimulatory signals such as CD28. Engagement of tumor necrosis factor receptor (TNFR) superfamily members, in particular TNFR2 and DR3, contribute to promote peripheral Tregs expansion and sustain their survival. This property can be leveraged to enhance tolerance to allogeneic transplants by tipping the balance of Tregs over conventional T cells during the course of immune reconstitution. This is of particular interest in peri-transplant tolerance induction protocols in which T cell depletion is applied to reduce the frequency of alloreactive T cells or in conditioning regimens that allow allogeneic bone marrow transplantation. These conditioning regimens are being implemented to limit long-term side effects of continuous immunosuppression and facilitate the establishment of a state of donor-specific tolerance. Lymphopenia-induced homeostatic proliferation in response to cytoreductive conditioning is a window of opportunity to enhance preferential expansion of Tregs during homeostatic proliferation that can be potentiated by agonist stimulation of TNFR.

The forces driving clonal expansion of the HIV-1 latent reservoir.

Despite antiretroviral therapy (ART) which halts HIV-1 replication and reduces plasma viral load to clinically undetectable levels, viral rebound inevitably occurs once ART is interrupted. HIV-1-infected cells can undergo clonal expansion, and these clonally expanded cells increase over time. Over 50% of latent reservoirs are maintained through clonal expansion. The clonally expanding HIV-1-infected cells, both in the blood and in the lymphoid tissues, contribute to viral rebound. The major drivers of clonal expansion of HIV-1-infected cells include antigen-driven proliferation, homeostatic proliferation and HIV-1 integration site-dependent proliferation. Here, we reviewed how viral, immunologic and genomic factors contribute to clonal expansion of HIV-1-infected cells, and how clonal expansion shapes the HIV-1 latent reservoir. Antigen-specific CD4+ T cells specific for different pathogens have different clonal expansion dynamics, depending on antigen exposure, cytokine profiles and exhaustion phenotypes. Homeostatic proliferation replenishes the HIV-1 latent reservoir without inducing viral expression and immune clearance. Integration site-dependent proliferation, a mechanism also deployed by other retroviruses, leads to slow but steady increase of HIV-1-infected cells harboring HIV-1 proviruses integrated in the same orientation at specific sites of certain cancer-related genes. Targeting clonally expanding HIV-1 latent reservoir without disrupting CD4+ T cell function is a top priority for HIV-1 eradication.

Physiology and pathology of T-cell aging.

Acquired immune function shows recognizable changes over time with organismal aging. These changes include T-cell dysfunction, which may underlie diminished resistance to infection and possibly various chronic age-associated diseases in the elderly. T-cell dysfunction may occur at distinct stages, from naive cells to the end stages of differentiation during immune responses. The thymus, which generates naive T cells, shows unusually early involution resulting in progressive reduction of T-cell output after adolescence, but peripheral T-cell numbers are maintained through antigen-independent homeostatic proliferation of naive T cells driven by the major histocompatibility complex associated with self-peptides and homeostatic cytokines, retaining the diverse repertoire. However, extensive homeostatic proliferation may lead to the emergence of dysfunctional CD4+ T cells with features resembling senescent cells, termed senescence-associated T (SA-T) cells, which increase and accumulate with age. In situations such as chronic viral infection, T-cell dysfunction may also develop via persistent antigen stimulation, termed exhaustion, preventing possible immunopathology due to excessive immune responses. Exhausted T cells are developed through the effects of checkpoint receptors such as PD-1 and may be reversed with the receptor blockade. Of note, although defective in their regular T-cell antigen-receptor-mediated proliferation, SA-T cells secrete abundant pro-inflammatory factors such as osteopontin, reminiscent of an SA-secretory phenotype. A series of experiments in mouse models indicated that SA-T cells are involved in systemic autoimmunity as well as chronic tissue inflammation following tissue stresses. In this review, we discuss the physiological aspects of T-cell dysfunction associated with aging and its potential pathological involvement in age-associated diseases and possibly cancer.

Spontaneous Proliferation of CD4+ T Cells in RAG-Deficient Hosts Promotes Antigen-Independent but IL-2-Dependent Strong Proliferative Response of Naïve CD8+ T Cells.

The fast and intense proliferative responses have been well documented for naïve T cells adoptively transferred into chronic lymphopenic hosts. This response known as spontaneous proliferation (SP), unlike antigen-independent lymphopenia-induced proliferation (LIP), is driven in a manner dependent on antigens derived from commensal microbiota. However, the precise nature of the SP response and its impact on homeostasis and function for T cells rapidly responding under this lymphopenic condition are still unclear. Here we demonstrate that, when naïve T cells were adoptively transferred into specific pathogen-free (SPF) but not germ-free (GF) RAG-/- hosts, the SP response of these cells substantially affects the intensity and tempo of the responding T cells undergoing LIP. Therefore, the resulting response of these cells in SPF RAG-/- hosts was faster and stronger than the typical LIP response observed in irradiated B6 hosts. Although the intensity and tempo of such augmented LIP in SPF RAG-/- hosts were analogous to those of antigen-dependent SP, the former was independent of antigenic stimulation but most importantly, dependent on IL-2. Similar observations were also apparent in other acute lymphopenic settings where antigen-dependent T cell activation can strongly occur and induce sufficient levels of IL-2 production. Consequently, the resulting T cells undergoing IL-2-driven strong proliferative responses showed the ability to differentiate into functional effector and memory cells that can control infectious pathogens. These findings therefore reveal previously unappreciated role of IL-2 in driving the intense form of T cell proliferative responses in chronic lymphopenic hosts.