Cell surface levels of endothelial ICAM‐1 influence the transcellular or paracellular T‐cell diapedesis across the blood–brain barrier

The extravasation of CD4⁺ effector/memory T cells (T_EM cells) across the blood–brain barrier (BBB) is a crucial step in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) or multiple sclerosis (MS). Endothelial ICAM‐1 and ICAM‐2 are essential for CD4⁺ T_EM cell crawling on the BBB prior to diapedesis. Here, we investigated the influence of cell surface levels of endothelial ICAM‐1 in determining the cellular route of CD4⁺ T_EM‐cell diapedesis across cytokine treated primary mouse BBB endothelial cells under physiological flow. Inflammatory conditions, inducing high levels of endothelial ICAM‐1, promoted rapid initiation of transcellular diapedesis of CD4⁺ T cells across the BBB, while intermediate levels of endothelial ICAM‐1 favored paracellular CD4⁺ T‐cell diapedesis. Importantly, the route of T‐cell diapedesis across the BBB was independent of loss of BBB barrier properties. Unexpectedly, a low number of CD4⁺ T_EM cells was found to cross the inflamed BBB in the absence of endothelial ICAM‐1 and ICAM‐2 via an obviously alternatively regulated transcellular pathway. In vivo, this translated to the development of ameliorated EAE in ICAM‐1^null//ICAM‐2^?/?C57BL/6J mice. Taken together, our study demonstrates that cell surface levels of endothelial ICAM‐1 rather than the inflammatory stimulus or BBB integrity influence the pathway of T‐cell diapedesis across the BBB.     

Stress‐activated dendritic cells interact with CD4+ T cells to elicit homeostatic memory

Evidence is presented that thermal or oxidizing stress‐activated DC interact with CD4⁺ T cells to induce and maintain a TCR‐independent homeostatic memory circuit. Stress‐activated DC expressed endogenous intra‐cellular and cell surface HSP70. The NF‐κB signalling pathway was activated and led to the expression of membrane‐associated IL‐15 molecules. These interacted with the IL‐15 receptor complex on CD4⁺ T cells, thus activating the Jak3 and STAT5 phosphorylation signalling pathway to induce CD40 ligand expression, T‐cell proliferation and IFN‐γ production. CD40 ligand on CD4⁺ T cells in turn re‐activated CD40 molecules on DC, inducing DC maturation and IL‐15 expression thereby maintaining the feedback circuit. The proliferating CD4⁺ T cells were characterized as CD45RA^? CD62L⁺ central memory cells, which underwent homeostatic proliferation. The circuit is independent of antigen and MHC‐class‐II‐TCR interaction as demonstrated by resistance to TCR inhibition by ZAP70 inhibitor or MHC‐class II antibodies. These findings suggest that stress can activate a DC‐CD4⁺ T‐cell interacting circuit, which may be responsible for maintaining a homeostatic antigen‐independent memory.     

Marked enhancement of antigen‐specific T‐cell responses by IL‐7‐fused nonlytic,but not lytic,Fc as a genetic adjuvant

IL‐7 plays a crucial role in the homeostatic proliferation, differentiation and survival of T cells, as well as in the survival and proliferation of precursor B cells. Here, we demonstrated that utilizing nonlytic Fc‐fused IL‐7 (IL‐7‐Fc^m) as a genetic adjuvant significantly enhanced not only CD4⁺ but also CD8⁺ T‐cell responses by E7 DNA immunization, in addition to improving protection against TC‐1‐induced tumors in comparison to IL‐7 alone. Similar results were obtained in OT‐1 adoptive transfer experiments with OVA DNA injection, suggesting independence from antigenic nature and experimental conditions. In particular, the increased frequency of CD8⁺ T cells was mainly due to enhanced T‐cell proliferation in T‐cell priming, and not to decreased cellular apoptosis. Interestingly, the enhanced adjuvant effect was not seen in the co‐delivery of lytic Fc‐fused IL‐7 (IL‐7‐Fc) which increases T‐cell apoptosis as well as T‐cell proliferation, suggesting that the T‐cell proliferative effect may be neutralized by T‐cell apoptosis. Thus, our findings suggest that nonlytic Fc, in contrast to lytic Fc, fusion to cytokines may provide an insight in designing a potent genetic adjuvant for inducing CD4⁺ and CD8⁺ T‐cell responses.     

CCR7+ Central and CCR7− Effector Memory CD4+ T Cells in Human Cutaneous Leishmaniasis

Purpose

The profile of central (=T_CM) and effector (=T_EM) memory CD4⁺ T cell subsets and the possible role as surrogate markers of protection is studied in the volunteers with history of cutaneous leishmaniasis (HCL).

Methods

Profile of T cell subsets based on CCR7/CD45RA expressions and phenotypic changes after soluble Leishmania antigen (SLA) stimulation were analyzed. Then, sorted CD4⁺CD45RO^?CD45RA⁺ naïve T, CD4⁺CD45RO⁺CD45RA^?CCR7^? T_EM, CD4⁺CD45RO⁺CD45RA^?CCR7⁺ T_CM subsets were cultured with SLA for proliferation, cytokine production and intracellular cytokine assays.

Results

In the HCL and control volunteers, the mean frequencies of CD4⁺CD45RA⁺CCR7⁺ naïve T cells and CD4⁺CD45RA^?CCR7^? T_EM cells were higher than the other subsets before culture. Frequency of naïve T cells and CD4⁺CD45RA^?CCR7⁺ T_CM cells was significantly decreased (P?=?0.01 for naïve T and P?<?0.05 for T_CM cells) and frequency of T_EM cells was significantly increased after SLA stimulation compared to before culture (P?<?0.001). By CFSE labeling, CD4⁺CD45RO⁺CD45RA^?CCR7⁺ T_CM cells showed more proliferation potential than CD4⁺CD45RO⁺CD45RA^?CCR7^? T_EM cells. Stimulation of the T_EM cells in HCL volunteers induced a significantly higher IFN-γ production (P?=?0.04) with higher number of intracellular IFN-γ positive cells (P?=?0.032) than the same cells from controls. A significantly higher number of T_CM cells produced IL-2 in HCL volunteers compared with controls (P?<?0.05). Most of the intracellular IFN-γ positive T_EM cells were proliferating CFSE-dim populations (P?<?0.05).

Conclusions

A combination of Leishmania-reactive IFN-γ producing CD4⁺CD45RO⁺CD45RA^?CCR7^? T_EM and Leishmania-reactive IL-2 producing CD4⁺CD45RO⁺CD45RA^?CCR7⁺ T_CM are identified in individuals with history of CL which might play a role in protective recall immune response against Leishmania infection.     

Could a loss of memory T cells limit responses to hepatitis C virus (HCV) antigens in blood leucocytes from patients chronically infected with HCV before and during pegylated interferon-α and ribavirin therapy?

The proportions and activation status of T cells may influence responses to hepatitis C virus (HCV) and treatment outcome in patients receiving pegylated interferon (IFN)‐α/ribavirin therapy. We confirmed that IFN‐γ enzyme‐linked immunospot (ELISPOT) responses to HCV are poor in HCV patients and showed that responses to HCV and cytomegalovirus (CMV) antigens decrease during therapy. This was most apparent in patients with sustained virological response (SVR). Baseline frequencies of CD4⁺ effector memory (T_EM) T cells were lower in SVR than non‐SVR. Proportions of CD4⁺ and CD8⁺ T_EM and terminally differentiated effector memory (T_EMRA) T cells declined on therapy in SVR, as did proportions of Fas⁺ CD8⁺ T_EMRA T cells. Baseline frequencies of programmed death (PD)‐1‐expressing CD4⁺ T_EM and T_EMRA T‐cells were higher in SVR. Therapy increased percentages of PD‐1⁺ CD4⁺ central memory (T_CM) T cells and PD‐1⁺ CD8⁺ T_EM and T_EMRA T cells in SVR. We conclude that successful therapy depletes circulating antigen‐specific CD4⁺ T cell responses. This paralleled decreases in proportions of effector memory T cells and higher percentages of CD4⁺ T_CM T cells expressing PD‐1.     

CD4+ CD25+ Treg regulate the contribution of CD8+ T-cell subsets in repopulation of the lymphopenic environment

Peripheral T‐cell expansion is of major relevance for immune function after lymphopenia. In order to promote regeneration, the process should result in a peripheral T‐cell pool with a similar subpopulation structure as before lymphopenia. We investigated the repopulation of the CD8⁺ central‐memory T cells (T_CM) and effector‐memory T cells (T_EM) pools after adoptive transfer of sorted CD8⁺ T cells from naïve, T_CM and T_EM subsets into T‐cell‐deficient hosts. We show that the initial kinetics of expansion are distinct for each subset and that the contribution to the repopulation of the CD8⁺ T‐cell pool by the progeny of each subset is not a mere function of its initial expansion. We demonstrate that CD4⁺CD25⁺ Treg play a major role in the repopulation of the CD8⁺ T‐cell pool and that CD8⁺ T‐cell subsets impact on each other. In the absence of CD4⁺CD25⁺ Treg, a small fraction of naïve CD8⁺ T cells strongly proliferates, correlating with further expansion and differentiation of co‐expanding CD8⁺ T cells. CD4⁺CD25⁺ Treg suppress these responses and lead to controlled repopulation, contributing decisively to the maintenance of recovered T_CM and T_EM fractions, and leading to repopulation of each pool with progeny of its own kind.     

n‐Butyrate Anergized Effector CD4+ T Cells Independent of Regulatory T cell Generation or Activity

CD4⁺ T cell anergy reflects the inability of CD4⁺ T cells to respond functionally to antigenic stimulation through proliferation or IL‐2 secretion. Histone deacetylase (HDAC) inhibitors have been shown to induce anergy in antigen‐activated CD4⁺ T cells. However, questions remain if HDAC inhibitors mediate anergy through direct action upon activated CD4⁺ T cells or through the generation and/or enhancement of regulatory T (T_reg) cells. To assess if HDAC inhibitor n‐butyrate induces anergy independent of the generation or expansion of FoxP3⁺ T_reg cells in vitro, we examine n‐butyrate‐treated murine CD4⁺ T cells for anergy induction and FoxP3⁺ T_reg activity. Whereas n‐butyrate decreases CD4⁺ T cell proliferation and IL‐2 secretion, n‐butyrate did not augment FoxP3 protein production or confer a suppressive phenotype upon CD4⁺ T cells. Collectively, these data suggest that HDAC inhibitors can facilitate CD4⁺ T cell functional unresponsiveness directly and independently of T_reg cell involvement.     

Programmed death (PD)‐1 molecule and its ligand PD‐L1 distribution among memory CD4 and CD8 T cell subsets in human immunodeficiency virus‐1‐infected individuals

Human immunodeficiency virus (HIV)‐1 causes T cell anergy and affects T cell maturation. Various mechanisms are responsible for impaired anti‐HIV‐1‐specific responses: programmed death (PD)‐1 molecule and its ligand PD‐L1 are negative regulators of T cell activity and their expression is increased during HIV‐1 infection. This study examines correlations between T cell maturation, expression of PD‐1 and PD‐L1, and the effects of their blockade. Peripheral blood mononuclear cells (PBMC) from 24 HIV‐1⁺ and 17 uninfected individuals were phenotyped for PD‐1 and PD‐L1 expression on CD4⁺ and CD8⁺ T cell subsets. The effect of PD‐1 and PD‐L1 blockade on proliferation and interferon (IFN)‐γ production was tested on eight HIV‐1⁺ patients. Naive (CCR7⁺CD45RA⁺) CD8⁺ T cells were reduced in HIV‐1 aviraemic (P = 0·0065) and viraemic patients (P = 0·0130); CD8 T effector memory subsets [CCR7^‐CD45RA^–(T_EM)] were increased in HIV‐1⁺ aviraemic (P = 0·0122) and viraemic (P = 0·0023) individuals versus controls. PD‐1 expression was increased in CD4 naive (P = 0·0496), central memory [CCR7⁺CD45RA^– (T_CM); P = 0·0116], T_EM (P = 0·0037) and CD8 naive T cells (P = 0·0133) of aviraemic HIV‐1⁺versus controls. PD‐L1 was increased in CD4 T_EMRA (CCR7^‐CD45RA⁺, P = 0·0119), CD8 T_EM (P = 0·0494) and CD8 T_EMRA (P = 0·0282) of aviraemic HIV‐1⁺versus controls. PD‐1 blockade increased HIV‐1‐specific proliferative responses in one of eight patients, whereas PD‐L1 blockade restored responses in four of eight patients, but did not increase IFN‐γ‐production. Alteration of T cell subsets, accompanied by increased PD‐1 and PD‐L1 expression in HIV‐1 infection contributes to anergy and impaired anti‐HIV‐1‐specific responses which are not rescued when PD‐1 is blocked, in contrast to when PD‐L1 is blocked, due possibly to an ability to bind to receptors other than PD‐1.     

Prolonged exposure of naïve CD8+ T cells to interleukin-7 or interleukin-15 stimulates proliferation without differentiation or loss of telomere length

Interleukin (IL)‐7 and IL‐15 are cytokines implicated in homeostatic control of the peripheral CD8 T‐cell pool. We compared the effects of IL‐7 and IL‐15 on survival and proliferation of purified human CD8⁺ T‐cell subsets. Low concentrations of either cytokine reduced the spontaneous apoptosis of all subsets, and enhancement of survival corresponded to the extent of Bcl‐2 up‐regulation. Surprisingly, although minimal proliferation of naïve CD8⁺ T cells was observed during the first week of culture with cytokines, a marked expansion of these cells occurred at later time points, particularly in response to IL‐15. This occurred largely without phenotypic change or acquisition of effector function, indicating a dissociation of differentiation from proliferation. Notably, progression of naïve CD8⁺ T cells through several cell divisions resulted in up‐regulation of telomerase and the maintenance of telomere length. These data show that IL‐7 and IL‐15 induce cell proliferation and rescue from apoptosis in a concentration, time and subset‐dependent manner, and have implications for the homeostatic expansion of the naïve CD8⁺ T‐cell pool.     

CMV drives the expansion of highly functional memory T cells expressing NK‐cell receptors in renal transplant recipients

Cytomegalovirus (CMV) is a common opportunistic infection encountered in renal transplant recipients (RTRs) and may be reactivated without symptoms at any time post‐transplant. We describe how active and latent CMV affect T‐cell subsets in RTRs who are stable on maintenance therapy. T‐cell responses to CMV were assessed in RTRs (n = 54) >2 years post‐transplant, and healthy controls (n = 38). Seven RTRs had CMV DNA detectable in plasma. CMV antibody and DNA aligned with increased proportions of CD8⁺ T cells and reduced CD4/CD8 ratios. This paralleled an expansion of effector memory T‐cell (T_EM), terminally differentiated T‐cell (T_EMRA) and CD57⁺ T_EMRA cell populations. Expression of NK‐cell receptors, LIR‐1 and KLRG1 on CD4⁺ and CD8⁺ CD57⁺ T_EM and T_EMRA cells correlated with elevated interferon‐γ and cytotoxic responses to anti‐CD3 and increased cytotoxic responses to CMV phosphoprotein (pp) 65 in RTRs who carried CMV DNA. CD8⁺ T cells from all CMV seropositive RTRs responded efficiently to CMV immediate early (IE) ‐1 peptides. The data show that latent and active CMV infection can alter T‐cell subsets in RTRs many years after transplantation, and up‐regulate T‐cell expression of NK‐cell receptors. This may enhance effector responses of CD4⁺ and CD8⁺ T cells against CMV.     

The transduction pattern of IL‐12‐encoding lentiviral vectors shapes the immunological outcome

In situ modification of antigen‐presenting cells garnered interest in cancer immunotherapy. Therefore, we developed APC‐targeted lentiviral vectors (LVs). Unexpectedly, these LVs were inferior vaccines to broad tropism LVs. Since IL‐12 is a potent mediator of antitumor immunity, we evaluated whether this proinflammatory cytokine could enhance antitumor immunity of an APC‐targeted LV‐based vaccine. Therefore, we compared subcutaneous administration of broad tropism LVs (VSV‐G‐LV) with APC‐targeted LVs (DC2.1‐LV)‐encoding enhanced GFP and ovalbumin, or IL‐12 and ovalbumin in mice. We show that codelivery of IL‐12 by VSV‐G‐LVs or DC2.1‐LVs augments CD4⁺ or CD8⁺ T‐cell proliferation, respectively. Furthermore, we demonstrate that codelivery of IL‐12 enhances the CD4⁺ T_H1 profile irrespective of its delivery mode, while an increase in cytotoxic and therapeutic CD8⁺ T cells was only induced upon VSV‐G‐LV injection. While codelivery of IL‐12 by DC2.1‐LVs did not enhance CD8⁺ T‐cell performance, it increased expression of inhibitory checkpoint markers Lag3, Tim3, and PD‐1. Finally, the discrepancy between CD4⁺ T‐cell stimulation with and without functional CD8⁺ T‐cell stimulation by VSV‐G‐ and DC2.1‐LVs is partly explained by the observation that IL‐12 relieves CD8⁺ T cells from CD4⁺ T‐cell help, implying that a T_H1 profile is of minor importance for antitumor immunotherapy if IL‐12 is exogenously delivered.     

Antigen‐specific over‐expression of human cartilage glycoprotein 39 on CD4+CD25+ forkhead box protein 3+ regulatory T cells in the generation of glucose‐6‐phosphate isomerase‐induced arthritis

Human cartilage gp‐39 (HC gp‐39) is a well‐known autoantigen in rheumatoid arthritis (RA). However, the exact localization, fluctuation and function of HC gp‐39 in RA are unknown. Therefore, using a glucose‐6‐phosphate isomerase (GPI)‐induced model of arthritis, we investigated these aspects of HC gp‐39 in arthritis. The rise in serum HC gp‐39 levels was detected on the early phase of GPI‐induced arthritis (day 7) and the HC gp‐39 mRNA was increased significantly on splenic CD4⁺T cells on day7, but not on CD11b⁺cells. Moreover, to identify the characterization of HC gp‐39⁺CD4⁺T cells, we assessed the analysis of T helper (Th) subsets. As a result, HC gp‐39 was expressed dominantly in CD4⁺CD25⁺ forkhead box protein 3 (FoxP3)⁺ refulatory T cells (T_reg), but not in Th1, Th2 or Th17 cells. Furthermore, to investigate the effect of HC gp‐39 to CD4⁺T cells, T cell proliferation assay and cytokine production from CD4⁺T cells using recombinant HC gp‐39 was assessed. We found that GPI‐specific T cell proliferation and interferon (IFN)‐γ or interleukin (IL)‐17 production were clearly suppressed by addition of recombinant HC gp‐39. Antigen‐specific over‐expression of HC gp‐39 in splenic CD4⁺CD25⁺ FoxP3⁺ T_reg cells occurs in the induction phase of GPI‐induced arthritis, and addition of recombinant HC gp‐39 suppresses antigen‐specific T‐cell proliferation and cytokine production, suggesting that HC gp‐39 in CD4⁺ T cells might play a regulatory role in arthritis.     

Generation of specific effector and memory T cells with gut- and secondary lymphoid tissue- homing potential by oral attenuated CVD 909 typhoid vaccine in humans

Induction of effective memory T cells is likely to be critical to the level and duration of protection elicited by novel live oral typhoid vaccines. Using cells from volunteers who ingested Salmonella Typhi vaccine strain CVD 909, we characterized the induction of interferon (IFN)-γ-secreting central (T_CM, CD45RO⁺CD62L⁺) and effector (T_EM, CD45RO⁺CD62L⁻) memory T populations, and their gut-homing potential based on integrin α4/β7 expression. Both CD4⁺ T_EM and T_CM populations secreted IFN-γ. However, although CD4⁺ T_EM expressed, or not, integrin α₄/β₇, CD4⁺ T_CM cells were predominantly integrin α₄/β₇⁺. In contrast, IFN-γ-secreting CD8⁺ cells were predominantly classical T_EM and CD45RA⁺ T_EM (T_EMRA, CD45RO⁻CD62L⁻) subsets. However, although CD8⁺ T_EM expressed, or not, integrin α₄/β₇, CD8⁺ T_EMRA were predominantly integrin α₄/β₇⁺. This is the first demonstration that oral immunization of humans with S. Typhi elicits diverse IFN-γ-secreting CD4⁺ and CD8⁺ T_CM and T_EM subsets able to migrate to the gut and other lymphoid tissues.     

Homeostasis of memory T cells

Summary: The pool of memory T cells is regulated by homeostatic mechanisms to persist for prolonged periods at a relatively steady overall size. Recent work has shown that two members of the common γ chain (γc) family of cytokines, interleukin‐7 (IL‐7) and IL‐15, govern homeostasis of memory T cells. These two cytokines work in conjunction to support memory T‐cell survival and intermittent background proliferation. Normal animals contain significant numbers of spontaneously arising memory‐phenotype (MP) cells, though whether these cells are representative of true antigen‐specific memory T cells is unclear. Nevertheless, it appears that the two types of memory cells do not display identical homeostatic requirements. For antigen‐specific memory CD8⁺ T cells, IL‐7 is primarily important for survival while IL‐15 is crucial for their background proliferation. For memory CD4⁺ T cells, IL‐7 has an important role, whereas the influence of IL‐15 is still unclear.     

Cells with regulatory function of the innate and adaptive immune system in primary Sjögren's syndrome

The aim of the present study was to describe subsets of cells with regulatory properties in primary Sjögren's syndrome (pSS), and to correlate these cell populations with clinical symptoms. Among the 32 investigated patients, 23 had extraglandular manifestations (EGMs), while nine had only glandular symptoms. Twenty healthy individuals served as controls. The percentages of natural killer (NK), natural killer T cells (NK T), interleukin (IL)‐10 producing T regulatory type 1 (Tr1) cells and CD4⁺CD25⁺ regulatory T cells (T_reg) cells were determined by flow cytometry and serum cytokine levels of IL‐4, IL‐6, IL‐10, tumour necrosis factor (TNF)‐α and interferon (IFN)‐γ were evaluated by enzyme‐linked immunosorbent assay (ELISA). Functional tests were carried out to assess the suppressor properties of T_reg cells in patients and controls. Peripheral NK, NK T and Tr1 cell percentages were elevated in pSS, while CD4⁺CD25⁺ T_reg cells showed reduced frequencies in patients compared to controls. In pSS, elevated percentages of NK T, Tr1 and CD4⁺CD25⁺ T_reg cells were observed in patients with EGMs, when compared to patients with sicca symptoms only. CD4⁺CD25⁺ T_reg cell percentages showed a negative correlation with sialometry values. The in vitro functional assay demonstrated lower suppression activity of CD4⁺CD25⁺ T_reg cells in patients compared to controls. Serum IL‐6 and TNF‐α levels were elevated, while IL‐10 was decreased in patients compared to controls. Negative correlation was found between IL‐10 levels and the percentages of Tr1 cells. Changes in the investigated subsets of regulatory cells in pSS may contribute to the development and progression of the disease.     

Immunosuppressive evidence of Tityus serrulatus toxins Ts6 and Ts15: insights of a novel K+ channel pattern in T cells

The voltage‐gated potassium channel Kv1.3 is a novel target for immunomodulation of autoreactive effector memory T cells, which play a major role in the pathogenesis of autoimmune diseases. In this study, the Ts6 and Ts15 toxins isolated from Tityus serrulatus (Ts) were investigated for their immunosuppressant roles on CD4⁺ cell subsets: naive, effector (T_EF), central memory (T_CM) and effector memory (T_EM). The electrophysiological assays confirmed that both toxins were able to block Kv1.3 channels. Interestingly, an extended Kv channel screening shows that Ts15 blocks Kv2.1 channels. Ts6 and Ts15 significantly inhibit the proliferation of T_EM cells and interferon‐γ production; however, Ts15 also inhibits other CD4⁺ cell subsets (naive, T_EF and T_CM). Based on the Ts15 inhibitory effect of proliferation of all CD4⁺ cell subsets, and based on its blocking effect on Kv2.1, we investigated the Kv2.1 expression in T cells. The assays showed that CD4⁺ and CD8⁺ cells express the Kv2.1 channels mainly extracellularly with T_CM cells expressing the highest number of Kv2.1 channels. We also provide in vivo experimental evidence to the protective effect of Ts6 and Ts15 on delayed‐type hypersensitivity reaction. Altogether, this study presents the immunosuppressive behaviour of Ts6 and Ts15 toxins, indicating that these toxins could be promising candidates for autoimmune disease therapy. Moreover, this is the first report illustrating the involvement of a novel K⁺ channel subtype, Kv2.1, and its distribution in T‐cell subsets.     

Interleukin‐4 downregulates CD127 expression and activity on human thymocytes and mature CD8+ T cells

Signaling via the IL‐7 receptor complex (IL‐7Rα/CD127 and IL‐2Rγ/CD132) is required for T‐cell development and survival. Decreased CD127 expression has been associated with persistent viral infections (e.g. HIV, HCV) and cancer. Many IL‐2Rγ‐sharing (γ_C) cytokines decrease CD127 expression on CD4⁺ and CD8⁺ T cells in mice (IL‐2, IL‐4, IL‐7, IL‐15) and in humans (IL‐2, IL‐7), suggesting a common function. IL‐4 is of particular interest as it is upregulated in HIV infection and in thyroid and colon cancers. The role of IL‐4 in regulating CD127 expression and IL‐7 activity in human thymocytes and mature CD8⁺ T cells is unknown and was therefore investigated. IL‐4 decreased CD127 expression on all thymocyte subsets tested and only on naïve (CD45RA⁺) CD8⁺ T cells, without altering membrane‐bound CD127 mRNA expression. Pre‐treatment of thymocytes or CD8⁺ T cells with IL‐4 inhibited IL‐7‐mediated phosphorylation of STAT5 and decreased proliferation of CD8⁺ T cells. By downregulating CD127 expression and signaling on developing thymocytes and CD8⁺ T cells, IL‐4 is a potential contributor to impaired CD8⁺ T‐cell function in some anti‐viral and anti‐tumor responses. These findings are of particular consequence to diseases such as HIV, HCV, RSV, measles and cancer, in which CD127 expression is decreased, IL‐7 activity is impaired and IL‐4 concentrations are elevated.     

Low numbers of CD8+ T lymphocytes in hereditary haemochromatosis are explained by a decrease of the most mature CD8+ effector memory T cells

Low CD8⁺ T lymphocyte numbers have long been described in hereditary haemochromatosis (HH). Recently, two conserved haplotypes localized near the microsatellite D6S105 at the major histocompatibility complex (MHC) class I region were described predicting the clinical expression of HH and the CD8⁺ T lymphocyte numbers. The A‐A‐T haplotype was associated with a severe clinical expression of HH and low CD8⁺ T lymphocyte numbers, while the G‐G‐G haplotype was associated with a milder clinical expression of HH and high CD8⁺ T lymphocyte numbers. As CD8⁺ T lymphocytes are a very heterogeneous population, in this study we analysed the CD8⁺ subpopulations of naive, central memory (T_CM) and effector memory (T_EM), and further subsets of CD8⁺ T_EM cells in 47 HH patients and 68 controls. In addition, association studies were conducted between the conserved haplotypes and the CD8⁺ T cell subpopulations in HH. Variations of the numbers of naive and central memory cells with age were similar between HH patients and controls. For T_EM cells and the T_EM CD27^‐CD28^‐ subset no effect of age was observed in HH [R² = 0·001, not significant (n.s.) and R² = 0·01, n.s., respectively] contrasting with the increasing of these subpopulations with age in controls (R² = 0·09, P = 0·017 and R² = 0·22, P = 0·0005, respectively). Interestingly, patients homozygous for the A‐A‐T haplotype have lower numbers of CD8⁺ T_EM cells due especially to lower numbers of T_EM CD27^‐CD28^‐ (0·206 ± 0·119 and 0·066 ± 0·067 × 10⁶ cells/ml, respectively) than patients carrying the G‐G‐G haplotype (0·358 ± 0·195 and 0·246 ± 0·202 × 10⁶ cells/ml, respectively). This may suggest an inability of HH patients to differentiate the CD8⁺ T cells into the most mature phenotype.