A11 Tetramer-assisted characterization of Rta-specific CD8+ T-cell responses in healthy virus carriers

HLA Class I-restricted CD8(+) T-cell responses are believed to play an important role in controlling Epstein-Barr virus (EBV) infection, which has been consistently associated with nasopharyngeal carcinoma (NPC). Immediate early transactivator Rta of EBV has been shown to be associated with the reactivation of EBV from latency and drive the lytic cascade of EBV and comprise an important target for EBV-specific cellular cytotoxicity. Furthermore, BRLF1 is specifically expressed in NPC tumor cells. The protein product of BRLF1, Rta, could then be considered as a NPC tumor antigen. Therefore, cellular immunity against Rta represents a very important part of the immunity against NPC, as they should prevent the replication of EBV. In the present study, Rta-specific CD8(+) T-cell responses in healthy virus carriers were characterized by using A1101 tetramer containing the known Rta epitope ATIGTAMYK (134-142). We clearly showed A1101/ATIGTAMYK tetramer-reactive CD8(+) T cells in the circulation of healthy virus carriers, ranging from 2.13 to 9.03%. We then studied the expression of perforin and interferon-gamma (IFN-gamma) secretion in these Rta-specific T cells. Our study demonstrated that Rta-specific T cells are capable of IFN-gamma production and nearly 90% of the Rta-specific CD8(+) T cells expressed perforin. Presumably, these are the cells that play an important role in determining the initiation of the lytic cycle or the clearance of EBV.     

Circulating memory CD8+ T cells are limited in forming CD103+ tissue-resident memory T cells at mucosal sites after reinfection

Tissue-resident memory CD8⁺ T cells (T_RM) localize to barrier tissues and mediate local protection against reinvading pathogens. Circulating central memory (T_CM) and effector memory CD8⁺ T cells (T_EM) also contribute to tissue recall responses, but their potential to form mucosal T_RM remains unclear. Here, we employed adoptive transfer and lymphocytic choriomeningitis virus reinfection models to specifically assess secondary responses of T_CM and T_EM at mucosal sites. Donor T_CM and T_EM exhibited robust systemic recall responses, but only limited accumulation in the small intestine, consistent with reduced expression of tissue-homing and -retention molecules. Murine and human circulating memory T cells also exhibited limited CD103 upregulation following TGF-β stimulation. Upon pathogen clearance, T_CM and T_EM readily gave rise to secondary T_EM. T_CM also formed secondary central memory in lymphoid tissues and T_RM in internal tissues, for example, the liver. Both T_CM and T_EM failed to substantially contribute to resident mucosal memory in the small intestine, while activated intestinal T_RM, but not liver T_RM, efficiently reformed CD103⁺ T_RM. Our findings demonstrate that circulating T_CM and T_EM are limited in generating mucosal T_RM upon reinfection. This may pose important implications on cell therapy and vaccination strategies employing memory CD8⁺ T cells for protection at mucosal sites.     

CD8+ CD28- and CD8+ CD57+ T cells and their role in health and disease

Chronic antigenic stimulation leads to gradual accumulation of late-differentiated, antigen-specific, oligoclonal T cells, particularly within the CD8(+) T-cell compartment. They are characterized by critically shortened telomeres, loss of CD28 and/or gain of CD57 expression and are defined as either CD8(+) CD28(-) or CD8(+) CD57(+) T lymphocytes. There is growing evidence that the CD8(+) CD28(-) (CD8(+) CD57(+)) T-cell population plays a significant role in various diseases or conditions, associated with chronic immune activation such as cancer, chronic intracellular infections, chronic alcoholism, some chronic pulmonary diseases, autoimmune diseases, allogeneic transplantation, as well as has a great influence on age-related changes in the immune system status. CD8(+) CD28(-) (CD8(+) CD57(+)) T-cell population is heterogeneous and composed of various functionally competing (cytotoxic and immunosuppressive) subsets thus the overall effect of CD8(+) CD28(-) (CD8(+) CD57(+)) T-cell-mediated immunity depends on the predominance of a particular subset. Many articles claim that CD8(+) CD28(-) (CD8(+) CD57(+)) T cells have lost their proliferative capacity during process of replicative senescence triggered by repeated antigenic stimulation. However recent data indicate that CD8(+) CD28(-) (CD8(+) CD57(+)) T cells can transiently up-regulate telomerase activity and proliferate under certain stimulation conditions. Similarly, conflicting data is provided regarding CD8(+) CD28(-) (CD8(+) CD57(+)) T-cell sensitivity to apoptosis, finally leading to the conclusion that this T-cell population is also heterogeneous in terms of its apoptotic potential. This review provides a comprehensive approach to the CD8(+) CD28(-) (CD8(+) CD57(+)) T-cell population: we describe in detail its origins, molecular and functional characteristics, subsets, role in various diseases or conditions, associated with persistent antigenic stimulation.     

Tolerogenic dendritic cells impede priming of naïve CD8+ T cells and deplete memory CD8+ T cells

Type 1 diabetes is a T‐cell‐mediated autoimmune disease in which autoreactive CD8⁺ T cells destroy the insulin‐producing pancreatic beta cells. Vitamin D3 and dexamethasone‐modulated dendritic cells (Combi‐DCs) loaded with islet antigens inducing islet‐specific regulatory CD4⁺ T cells may offer a tissue‐specific intervention therapy. The effect of Combi‐DCs on CD8⁺ T cells, however, remains unknown. To investigate the interaction of CD8⁺ T cells with Combi‐DCs presenting epitopes on HLA class I, naive, and memory CD8⁺ T cells were co‐cultured with DCs and proliferation and function of peptide‐specific T cells were analyzed. Antigen‐loaded Combi‐DCs were unable to prime naïve CD8⁺ T cells to proliferate, although a proportion of T cells converted to a memory phenotype. Moreover, expansion of CD8⁺ T cells that had been primed by mature monocyte‐derived DCs (moDCs) was curtailed by Combi‐DCs in co‐cultures. Combi‐DCs expanded memory T cells once, but CD8⁺ T‐cell numbers collapsed by subsequent re‐stimulation with Combi‐DCs. Our data point that (re)activation of CD8⁺ T cells by antigen‐pulsed Combi‐DCs does not promote, but rather deteriorates, CD8⁺ T‐cell immunity. Yet, Combi‐DCs pulsed with CD8⁺ T‐cell epitopes also act as targets of cytotoxicity, which is undesirable for survival of Combi‐DCs infused into patients in therapeutic immune intervention strategies.     

Gene expression patterns associated with tumor-infiltrating CD4+ and CD8+ T cells in invasive breast carcinomas

BackgroundBreast carcinoma is one of the most common tumors in women. The immune microenvironment, especially T cell infiltration, is related to the occurrence and prognosis of breast carcinoma.ObjectiveThis study investigated the gene expression patterns associated with tumor-infiltrating CD4+ and CD8+ T cells in invasive breast carcinomas.MethodsThe gene expression data and corresponding clinical phenotype data from the Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) were downloaded. The stromal and immune score were calculated using ESTIMATE. The differentially expressed genes (DEGs) with a high vs. low stromal score and a high vs. low immune score were screened and then functionally enriched. The tumor-infiltrating immune cells were investigated using the Cibersort algorithm, and the CD4+ and CD8+ T cell-related genes were identified using a Spearman correlation test of infiltrating abundance with the DEGs. Moreover, the miRNA-mRNA pairs and lncRNA-miRNA pairs were predicted to construct the competing endogenous RNAs (ceRNA) network. Kaplan-Meier (K-M) survival curves were also plotted.ResultsIn total, 478 DEGs with a high vs. low stromal score and 796 DEGs with a high vs. low immune score were identified. In addition, 39 CD4+ T cell-related genes and 78 CD8+ T cell-related genes were identified; of these, 14 genes were significantly associated with the prognosis of BRCA patients. Moreover, for CD4+ T cell-related genes, the chr22-38_28785274-29006793.1–miR-34a/c-5p–CAPN6 axis was identified from the ceRNA network, whereas the chr22-38_28785274-29006793.1–miR-494-3p–SLC9A7 axis was identified for CD8+ T cell-related genes.ConclusionsThe chr22-38_28785274-29006793.1–miR-34a/c-5p–CAPN6 axis and the chr22-38_28785274-29006793.1–miR-494-3p–SLC9A7 axis might regulate cellular activities associated with CD4+ and CD8+ T cell infiltration, respectively, in BRCA.     

Ex vivo analysis of phenotype and TCR usage in relation to CD45 isoform expression on cytomegalovirus-specific CD8+ T lymphocytes

Human cytomegalovirus (CMV) is a ubiquitous pathogen which sets up a lifelong persistent infection and which can lead to significant disease in the immunosuppressed. The immunological mechanisms controlling CMV in the long term are not defined completely, but CD8+ T lymphocytes are thought to play an important role. Antiviral CD8+ T lymphocytes may exist in very large pools in healthy individuals. Although the detailed composition of these pools is not completely understood, there is known to be heterogeneity, in particular of CD45 isoform expression. We have therefore investigated the CD8+ T-lymphocyte response against CMV directly ex vivo using Class I tetramers combined with stains for a range of phenotypic markers followed by four-colour flow cytometric analysis. In particular, we examined expression of these phenotypic markers in relation to the expression of CD45 isoforms. We found that a spectrum of phenotypes exists stably, from CD45R0(high)/RA(low) through CD45RA(high)/R0(low), and that expression of other surface markers such as CD28 and CD62L, and also TCR usage, may vary in parallel with CD45 isoform expression. In some individuals, expansions of antigen-specific CD8+ T lymphocytes bearing specific TCR Vbeta chains were restricted to cells of particular CD45 isoforms. Immunity against CMV comprises a large population of CD8+ T lymphocytes with heterogeneous potential, a spectrum in which CD45 isoform expression may play a central role.     

Subsets of CD8 +, CD57+ cells in normal,healthy individuals: correlations with human cytomegalovirus (HCMV) carrier status,phenotypic and functional analyses

Two different subsets of CD8 ⁺, CD57⁺ cells have been defined, one expressing high levels (CD8_high⁺(CD57⁺)), the other expressing low levels of surface CD8 (CD8_low⁺(CD57⁺)). Increased numbers of CD8_high⁺(CD57⁺) cells correlated with previous HCMV infection. By three-colour fluorescence analysis, the CD8_high⁺(CD57 ⁺) population expressed T cell markers such as CD3 and CD5, and most were αβ T cell receptor (αβ TCR)-positive. A significant proportion also expressed CD71 (transferrin receptor) and MHC class II, although little if any CD25 (IL-2R-p55). Some (≥ 40%) co-expressed CD45RA and CD45RO. The CD8_low⁺ (CD57⁺) population expressed classical natural killer (NK) cell markers—CD2, CD16 and CD56. The two subsets were also functionally distinct; CD8_high⁺ (CD57⁺) cells suppressed pokeweed mitogen (PWM)-driven, but not phytohaem-agglutinin (PHA)-driven proliferation and immunoglobulin production; CD8_low⁺ (CD57⁺) cells exhibited NK cytotoxic activity which was not increased by interferon-alpha (IFN-α). Supernatant from cultured CD8_high⁺ (CD57⁺) cells suppressed PWM-driven immunoglobulin production, but not proliferation, and this effect was abrogated by physical separation with tissue culture inserts. Thus, a T cell subset expressing activation and memory T cell markers with direct non-specific suppressor activity was present in peripheral blood mononuclear cells (PBMC) of healthy subjects with asymptomatic HCMV infection.     

Definition of the HLA-A2 restricted peptides recognized by human CD8+ effector T cells by flow-assisted sorting of the CD8+ CD45RA+ CD28- T cell subpopulation

In response to antigenic stimulation, naive MHC-class I restricted and antigen-specific CD8+ CD45RA+ CD28+ T cells undergo clonal expansion, differentiate into CD8+ CD45RO+ memory T cells and convert to CD8+ CD45RA+ CD28- T cells displaying potent immune effector functions upon re-encounter with the nominal antigen. We show that the effector CD8+ CD45RA+ CD28- T cell subset is expanded in peripheral blood lymphocytes (PBL) from patients with human papilloma virus (HPV)+ cervical lesions as well as in PBL from patients with pulmonary tuberculosis. Flow-cytometric cell sorted CD8+ CD45RA+ CD28- and CD8+ CD45RA+ CD28- T cells were tested for recognition of HLA-A2 restricted peptides derived either from the human papillomavirus (HPV)16-E7 gene product, or from M. tuberculosis antigens. Mostly CD8+ CD45+ CD28- T cells define antigen/peptide-specific and MHC-restricted responses. These data were confirmed in PBL from patients with tuberculosis using HLA-A2 tetramer-complexes loaded with a peptide from the M. tuberculosis Ag85b antigen by flow cytometry. The sorting of this T cell subset enables to determine the fine specificity of CD8+ effector T cells without the need for in vitro manipulation.     

多参数分析多发性骨髓瘤患者外周血中CD4~+CD25~+调节性T细胞的表达

目的 通过分析CD4+ CD25+ 调节性T细胞(CD4+ CD25+ regulatory T cells,CD4+ CD25+ Tress)在不同病程阶段多发性骨髓瘤(multiple myeloma,MM)患者外周血中的变化和临床意义,初步探讨MM患者的免疫抑制机制.方法 流式细胞术检测56例MM患者及30例健康志愿者外周血CD4+ CD25+、CD4+ CD25high、CD4+ CD25+ CD127low、CD4+ CD25high CD127low T细胞的比例并分析比较.结果 1)56例MM患者:化疗后组CD4+ CD25+、CD4+ CD25high、CD4+ CD25+ CD127low、CD4+ CD25high CD127low T 细胞的比例均高于正常组,差异具有显著性;初诊组的CD4+ CD25+ CD127low T细胞与正常对照组比较没有差异,但CD4+CD25+、CD4+ CD25high、CD4+ CD25high CD127lwo T细胞与正常对照组比较差异具有显著性;初诊组CD4+ CD25+T细胞的比例与化疗后组相比没有差异,但其CD4+ CD25high 、CD4+ CD25+ CD127low、CD4+ CD25high CD127low T细胞的比例均低于化疗后组,差异具有统计学意义.2)37例化疗后MM患者:稳定期与活动期的CD4+ CD25+、CD4+CD25+CD127low T细胞相比没有差异,但稳定期的CD4+ CD25high、CD4+ CD25high CD127low T细胞明显低于活动期.结论 CD4+ CD25+ Tregs在MM患者外周血中比例明显升高,且化疗可能影响其在外周血的比例;活动期MM患者CD4+ CD25+ Tregs的比例明显高于稳定期.这些提示CD4+ CD25+ Tregs可能是MM免疫抑制的一个重要原因.     

Proliferation and interleukin 5 production by CD8hi CD57+ T cells

CD8hi CD57+ T cells have previously been described as effector memory T cells with minimal expansion capacity and high susceptibility to activation-induced cell death. In contrast, we demonstrate here that CD8hi CD57+ T cells are capable of rapid expansion using multiple techniques including [(3)H]thymidine uptake, flow cytometric bead-based enumeration and standard haemocytometer counting. Previous reports can be explained by marked inhibition of activation-induced expansion and increased 7-amino-actinomycin D uptake by CD8hi CD57+ T cells following treatment with CFSE, a dye previously used to measure their proliferation, combined with specific media requirements for the growth of this cell subset. The ability of CD8hi CD57+ T cells to further differentiate is highlighted by a distinct cytokine profile late after activation that includes the unexpected release of high levels of interleukin 5. These data indicate that CD8hi CD57+ T cells should not be considered as "end-stage" effector T cells incapable of proliferation, but represent a highly differentiated subset capable of rapid division and exhibiting novel functions separate from their previously described cytotoxic and IFN-gamma responses.     

Lower percentage of CD8+ T cells in peripheral blood of patients with sporotrichosis

PurposeTo characterize the peripheral immunity and immunity response of patients with sporotrichosis, in this study we determined the lymphocyte subsets in the peripheral blood of Chinese patients with sporotrichosis.MethodsIn this retrospective study, peripheral blood was collected from 69 sporotrichosis patients (37, fixed cutaneous form; 32 lymphocutaneous) and 66 healthy controls. Lymphocyte subsets were analyzed using flow cytometry.ResultsCompared to controls, the percentage of CD8+ T cells was lower in sporotrichosis patients. The percentage of CD8+ T cells in peripheral blood tended to become lower with disease duration and disease severity, although the difference was not statistically significant for either acute, subacute and chronic patients or fixed cutaneous and lymphocutaneous patients.ConclusionOur data indicate that the decrease of CD8+ T cells in peripheral blood of patients with sporotrichosis is associated with disease severity, although the difference was not statistically significant for either duration or clinical forms of the disease. Combining antifungal agents and immunomodulators in patients with long disease duration and lymphocutaneous may be more beneficial than antifungal monotherapy.     

系统性红斑狼疮患者外周血CD4+和CD8+T细胞PD-1的表达和意义

目的 探讨程序性死亡分子1 (PD-1)在系统性红斑狼疮(SLE)患者外周血CD4+和CD8+T细胞上的表达及临床意义.方法 应用流式细胞仪检测51例SLE患者和38例健康对照者外周血T细胞亚群表面PD-1表达水平,比较SLE稳定组、活动组和健康对照组以及狼疮肾炎组和无狼疮肾炎组之间CD4+和CD8+T细胞表面PD-1表达的百分比,并分析其与临床表现及实验室检查数据的相关性.结果 SLE活动组CD4+T细胞PD-1表达水平高于健康对照组和不活动组,差异均有统计学意义(P＜0.05).SLE活动组、稳定组CD8+T细胞PD-1表达水平均高于健康对照组,差异有统计学意义(P＜0.05).狼疮肾炎患者CD4+PD-1+和CD8+PD-1+T细胞分别高于无狼疮肾炎患者(P＜0.01).SLE患者中抗dsDNA抗体、抗Sm抗体、抗核小体抗体阳性组外周血CD4+和CD8+T细胞PD-1表达水平均高于对应阴性组.SLE患者CD4+和CD8+T细胞PD-1表达百分率与SLE疾病活动度指数(SLEDAI)、尿蛋白定量呈正相关,与补体C3呈负相关.结论 SLE患者外周血CD4+和CD8+T细胞PD-1表达异常,与SLEDA1和自身抗体产生有明确的相关性.     

CD8+ Treg cells suppress CD8+ T cell‐responses by IL‐10‐dependent mechanism during H5N1 influenza virus infection

Although Treg‐cell‐mediated suppression during infection or autoimmunity has been described, functions of Treg cells during highly pathogenic avian influenza virus infection remain poorly characterized. Here we found that in Foxp3‐GFP transgenic mice, CD8⁺ Foxp3⁺ Treg cells, but not CD4⁺ Foxp3⁺ Treg cells, were remarkably induced during H5N1 infection. In addition to expressing CD25, the CD8⁺ Foxp3⁺ Treg cells showed a high level of GITR and produced IL‐10. In an adoptive transfer model, CD8⁺ Treg cells suppressed CD8⁺ T‐cell responses and promoted H5N1 virus infection, resulting in enhanced mortality and increased virus load in the lung. Furthermore, in vitro neutralization of IL‐10 and studies with IL‐10R‐deficient mice in vitro and in vivo demonstrated an important role for IL‐10 production in the capacity of CD8⁺ Treg cells to inhibit CD8⁺ T‐cell responses. Our findings identify a previously unrecognized role of CD8⁺ Treg cells in the negative regulation of CD8⁺ T‐cell responses and suggest that modulation of CD8⁺ Treg cells may be a therapeutic strategy to control H5N1 viral infection.     

Origins and functional basis of regulatory CD11c+CD8+ T cells

Previously, we showed that CD11c defines a novel subset of CD8⁺ T cells whose in vivo activity is therapeutic for arthritis; however, the mechanisms directing their development, identity of their precursors, and basis of their effector function remain unknown. Here, we show that the novel subset develops from CD11c^surface?CD8⁺ T cells and undergoes robust expansion in an antigen‐ and 4‐1BB (CD137)‐dependent manner. CD11c⁺CD8⁺ T cells exist in naïve mice (<3%) with limited suppressive activity. Once activated, they suppress CD4⁺ T cells in vivo and in vitro. Suppression of CD4⁺ by CD11c⁺CD8⁺ T cells is related to an increase in IDO activity induced in competent cells via the general control non‐derepressible‐2 pathway. CD11c⁺CD8⁺ T cells are refractory to the effect of IDO but constrict in a novel 1‐methyl D ,L ‐tryptophan‐dependent mechanism resulting in reversal of their suppressive effects. Thus, our data uncover, for the first time, the origin, development, and basis of the suppressive function of this novel CD11c⁺CD8⁺ T‐cell subpopulation that has many signature features of Treg.     

免疫磁珠负性分离纯化小鼠脾脏CD8+ T细胞

目的 探讨小鼠脾脏CD8 T细胞的免疫磁珠负性分选方法,并对分选后所得细胞进行纯度、活力及功能检测.方法 以免疫磁珠负性分选法从小鼠脾脏细胞中分离CD8 T细胞,流式细胞术检测所得细胞的纯度,台盼蓝检测细胞活力并用ConA刺激检测增殖能力. 结果 经过流式细胞仪测定免疫磁珠负性分选后的小鼠脾脏CD8 T细胞纯度达到(91.6±3.6)%,台盼兰染色细胞活力为(94.9±3.2)%,ConA刺激72 h后有(56.3±1.7)%的细胞增殖.结论 免疫磁珠负性分选法能够分选出高纯度的CD8 T细胞,并且不影响分选靶细胞的细胞活力和功能.     

Peripheral CD4+ CD8- γδ T cell lymphoma: A case report with multiparameter analyses

A 72-year-old Japanese man presented with CD4+ T cell receptor (TCR) γδ T cell lymphoma involving bilateral cervical lymph nodes. No involvement by tumor was observed in the liver, spleen, nasal cavity, or bone marrow throughout his clinical course. Although the tumor adequately responded to chemotherapy and irradiation, he relapsed with short remission and a slowly aggressive clinical course, and died 24 months after onset. Simultaneous expression of TCRγδ with other T-cell antigens on the lymphoma cells was analyzed by 3-color flow cytometry (3-FCM), and showed a unique phenotype CD3+ CD4+ CD8− CD7− CD5+ CD2++ TCRαβ (WT31)- βF1-TCRγδ1 (11F2)+ TCRδ1+. Cytogenetic analysis showed 79–81 and structural abnormalities consisting of del(1) (p11) and i(17)(q10). But no abnormality was identified in chromosome 7. DNA analysis revealed gene rearrangements of TCRγ and δ, while a nongerm line band in TCRβ was aberrantly seen. These observations suggest a new subtype of γδ T-cell lymphoma, which is characterized by CD4 positivity and by a clinical course not as aggressive as other predominant subtypes.     

健康青年人HCMV特异性CD8+T细胞频率和表型分析

目的 利用负载pp65495.503抗原肽的HLA-A*0201四聚体染色结合流式细胞术,分析HLA-A2 健康青年供者外周血中HCMV pp65495-503特异性记忆CD8 T细胞的频率和表型.方法 以优化的四聚体染色方法对22例中国青年供者全血进行染色,用流式细胞仪对样品进行三色荧光分析.结果 健康中国青年人外周血中存在高频率的pp65495-503特异性CD8 T细胞,占CD8 T细胞的百分率为0.14～6.84%(均数2.45%);表型分析显示其CD28 细胞占四聚体阳性和四聚体阴性细胞的百分率分别为为32.5%(±21.7%)和58.58%(±10.4%)(P＜0.001);CD57 细胞占四聚体阳性和四聚体阴性细胞的百分率分别为55.8%(±18.4%)和27.4%(±8.3%)(P＜0.001).同时,对三例健康青年人CD8 T细胞上多种表面分子的详细分析显示,pp65495-503特异性记忆CD8 T细胞有不同比率的细胞表达CD62L、CD45RO、CD38和CD27,而且还有一定比例的细胞表达CD45RA,但不表达活化抗原CD69分子.结论 青年中国人外周血中存在高频率的HCMV特异性CD8 T细胞,这些细胞的表型存在高度异质性,可能是处于不同分化阶段的记忆和效应细胞群体组成.     

A correlation between function and selected measures of T cell avidity in influenza virus-specific CD8+ T cell responses

Activation of mature CD8+ T cells requires recognition, via the T cell receptor (TCR), of peptide + MHC (pMHC) complexes with an avidity that exceeds a designated threshold. Multiple indicators of T cell avidity have been described that provide unique information on the characteristics of T cell interactions. However, these indicators are routinely used in isolation, and, consequently, little is known about correlations between these measures or which measure, if any, correlates with the quality of the T cell response. Following influenza virus infection of C57BL/6J mice, we analyzed the relative avidities of five epitope-specific CD8+ T cell populations using five different measures. We demonstrated that the quality of CD8+ T cell responses, in terms of cytokine profiles, correlates with TCR dissociation rate and CD8 dependence, but not with the sensitivity to tetramer binding or peptide stimulation. Thus, we propose that, despite significant differences in TCR dissociation rate, the stimulation threshold of influenza-specific CD8+ T cell populations may be equivalent due to compensatory mechanisms largely provided by the CD8 coreceptor. Furthermore, this study shows that different indicators of avidity do not necessarily provide similar information and should be used in combination to obtain an overall picture of the characteristics of TCR binding.     

Non-antigen specific CD8+ T suppressor lymphocytes

Abstract. The homeostasis of peripheral immune system function is maintained by the activity of regulatory lymphocytes. Among these cells, a subset of CD8+CD28- T suppressor lymphocytes has recently been characterized for the capacity to mediate their effects without antigen restriction. These non-antigen-specific CD8+ T suppressor lymphocytes originate from circulating CD8+CD28- T lymphocytes after stimulation with interleukin-2 and interleukin- 10. CD8+ suppressor cells inhibit both antigen-specific CD4+ T cell proliferation and cellular cytoxicity through secretion of cytokines such as interferon-, interleukin-6, and interleukin-10. The function of CD8+ suppressor cells is impaired in patients with systemic lupus erythematosus in relapse as well as in patients with systemic sclerosis with disease progression, suggesting the involvement of CD8+ suppressor cells in the pathogenesis of autoimmune diseases. Interestingly, CD8+ suppressor cells have been found among tumor-infiltrating lymphocytes, which could be related to tumor-induced-immunosuppression. Failure to generate CD8+ suppressor cells from the peripheral blood is frequently observed in HIV-infected patients. It remains to be clarified whether this phenomenon is due to depletion and/or functional impairment of this cell subset or to their compartmentalization in peripheral tissues and immunocompetent organs where they could contribute to the induction of immunodeficiency.