Epigenomic-Guided Mass Cytometry Profiling Reveals Disease-Specific Features of Exhausted CD8 T Cells

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Decreased proportions of CD4 + IL17+/CD4 + CD25 + CD127− and CD4 + IL17+/CD4 + CD25 + CD127 − FoxP3+ T cells in children with autoimmune thyroid diseases*

Until now, altered balance of Th1 and Th2 immune cells has been postulated to play an important role in the pathogenesis of autoimmune thyroid diseases (AITD). However, recent studies on thyroid diseases have suggested a new role for Th17 cells that have been classified as a new lineage, distinct from Th1, Th2 and Treg cells. Despite wide interest, the role of Th17 cells in the pathogenesis of inflammatory and autoimmune diseases is still debated. The aim of the study was to estimate the proportions of Th17/Treg T cells in peripheral blood from patients with Graves’ disease (GD; n?=?29, mean age 15.4?±?5.1 years), Hashimoto’s thyroiditis (HT; n?=?39, mean age 15.2?±?4.1 years) and in healthy controls (n?=?49, mean age 14.8?±?3 years). Polychromatic flow cytometry and several fluorochrome-conjugated monoclonal antibodies were applied to delineate Th17 and Treg cells. The analysis of Th17/Treg T cell proportions in peripheral blood from patients with Graves’ disease revealed significantly lower ratios of CD4?+?IL17+/CD4?+?CD25?+?CD127???(p?p?p?p?R?=?0.71, p?R?=?0.72, p?R?=?0.66, p?相似文献   

Generation and Regulation of CD8＋ Regulatory T Cells

Research into the suppressive activity of CD4＋FoxP3＋ T regulatory cells （Treg） has defined a sublineage of CD4＋ cells that contribute to self-tolerance and resistance to autoimmune disease. Much less attention has been given to the potential contribution of regulatory sublineages of CD8＋ cells. Analysis of a small fraction of CD8＋ cells that target autoreactive CD4＋ cells through recognition of the MHC class Ib molecule Qa-1 in mouse and HLA-E in human has revitalized interest in CD8＋ Treg. Here we summarize recent progress and future directions of research into the role of this CD8＋ sublineage in resistance to autoimmune disease. Cellular ＆ Molecular Immunology. 2008; 5（6）：401-406.     

Pleural Mesothelial Cells Promote Expansion of IL-17–Producing CD8+ T Cells in Tuberculous Pleural Effusion

IL-17–producing CD8⁺ T lymphocytes (Tc17 cells) have recently been detected in many cancers and autoimmune diseases. However, the possible implication of Tc17 cells in tuberculous pleural effusion remains unclarified. In this study, distribution and phenotypic features of Tc17 cells in both tuberculous pleural effusion (TPE) and peripheral blood from patients with tuberculosis were determined. The effects of proinflammatory cytokines and local accessory cells (pleural mesothelial cells) on Tc17 cell expansion were also explored. We found that TPE contained more Tc17 cells than the blood. Compared with IFN-γ–producing CD8⁺ T cells, Tc17 cells displayed higher expression of chemokine receptors (CCRs) and lower expression of cytotoxic molecules. In particularly, Tc17 cells in TPE exhibited high expression levels of CCR6, which could migrate in response to CCL20. Furthermore, IL-1β, IL-6, IL-23, or their various combinations could promote Tc17 cell expansion from CD8⁺ T cells, whereas the proliferative response of Tc17 cells to above cytokines was lower than that of Th17 cells. Pleural mesothelial cells (PMCs) were able to stimulate Tc17 cell expansion via cell contact in an IL-1β/IL-6/IL-23 independent fashion. Thus this study demonstrates that Tc17 cells marks a subset of non-cytotoxic, CCR6⁺ CD8⁺ T lymphocytes with low proliferative capacity. The overrepresentation of Tc17 cells in TPE may be due to Tc17 cell expansion stimulated by pleural proinflammatory cytokines and to recruitment of Tc17 cells from peripheral blood. Additionally, PMCs may promote the production of IL-17 by CD8⁺ T cells at sites of TPE via cell–cell interactions.     

CXCR3 May Help Regulate the Inflammatory Response in Acute Lung Injury via a Pathway Modulated by IL-10 Secreted by CD8 + CD122+ Regulatory T Cells

The aim of this study is to investigate the role of CXCR3 and IL-10 in lipopolysaccharide (LPS)-induced acute lung injury (ALI). ALI was induced by LPS injection (10 mg/kg) via the tail vein in C57BL/6 mice. Mice were sacrificed after 2 or 12 h to examine the levels of inflammatory cytokines in bronchoalveolar lavage fluid (BALF) and histopathologic assessments. At 12 h after LPS injection, mice exhibited more severe lung infiltration by CD8+ T cell and less infiltration by CD8+CD122+ regulatory T cells than at 2 h after LPS challenge or in the control (mice not exposed to LPS). At 12 h, IFN-γ, CXCR3, and CXCL10 were significantly higher in the lungs. IL-10 in the lungs was significantly lower. CXCR3 may help to recruit CD8+ T cells and promotes IFN-γ and CXCL10 release. Such effects could be inhibited by IL-10 secreted by CD8+CD122+ regulatory T cells.     

CD4+CD7− T Cells: A Separate Subpopulation of Memory T Cells?

The CD7 molecule is apparently involved in T cell activation but is absent in a substantial subpopulation of human T cells under physiological and certain pathological conditions. The majority of CD7^– T cells expresses TCR / and is of CD4⁺ helper and CD45R0⁺CD45RA^– memory phenotype. After birth, percentages and absolute numbers of circulating CD7^– T cells increase significantly during aging. A number of molecules thought to be involved in organ-specific T cell homing are preferentially expressed within the subset of CD4⁺CD7^– T cells. Specific absence of CD7 antigen expression on T cells is observed in a variety of pathologic conditions such as cutaneous T cell lymphoma, HIV infection, rheumatoid arthritis, and kidney transplantation. Current in vitro results suggest that specific downregulation of CD7 antigen expression in T cells reflects a separate and stable differentiation state occurring late in the immune response. Expansion of CD7^– T cells in vivo has been found in certain diseases associated with chronically repeated T cell stimulation. The potential pathophysiological significance of this T cell subset in certain human diseases is discussed.     

Type 1 CD8^＋ T Cells are Superior to Type 2 CD8^＋ T Cells in Tumor Immunotherapy due to Their Efficient Cytotoxicity, Prolonged Survival and Type 1 Immune Modulation

CD8^＋ cytotoxic T （Tc） cells play a crucial role in host immune responses to cancer, and in this context, adoptive CD8^＋ Tc cell therapy has been studied in numerous animal tumor models. Its antitumor efficacy is, to a large extent, determined by the ability of Tc cells to survive and infiltrate tumors. In clinical trials, such in vitro-activated T cells often die within hours to days, and this greatly limits their therapeutic efficacy. CD8^＋ Tc cells fall into two subpopulations based upon their differential cytokine secretion. In this study, we in vitro generated that ovalbumin （OVA）-pulsed dendritic cell （DCovA）-activated CD8^＋ type 1 Tc （Tcl） cells secreting IFN-T, and CD8^＋ type 2 Tc （Tc2） cells secreting IL-4, IL-5 and IL-10, which were derived from OVA-specific T cell receptor （TCR） transgenic OT I mice. We then systemically investigated the in vitro and in vivo effector function and survival of Tcl and Tc2 cells, and then assessed their survival kinetics after adoptively transferred into C57BL/6 mice, respectively. We demonstrated that, when compared to CD8^＋ Tc2, Tcl cells were significantly more effective in perforin-mediated cytotoxicity to tumor cells, had a significantly higher capacity for in vivo survival after the adoptive T cell transfer, and had a significantly stronger therapeutic effect on eradication of well-established tumors expressing OVA in animal models. In addition, CD8^＋ Tcl and Tc2 cells skewed the phenotype of CD4^＋ T cells toward Thl and Th2 type, respectively. Therefore, the information regarding the differential effector function, survival and immune modulation of CD8^＋ Tcl and Tc2 cells may provide useful information when preparing in vitro DC-activated CD8^＋ T cells for adoptive T cell therapy of cancer.     

Peripheral distributions of IL-4-producing CD4 + T cells and CD4 + CD25 + FoxP3 + T cells (Tregs) in rheumatoid arthritis patients with poor response to therapy are associated with HLA shared epitope alleles and ACPA status

Specific profiling of CD4?+?T cell subsets in the circulation and inflamed joints of rheumatoid arthritis (RA) patients may have therapeutic implications. This study aimed to evaluate the peripheral distributions of Th2 and Treg cells in relation to HLA-shared epitope (SE) alleles and anti-cyclic citrullinated peptide antibody (ACPAs) status in patients with good response (GR) and poor response (PR) to treatment. The frequencies of IL-4-producing CD4?+?T cells (Th2) and CD4?+?CD25?+?Foxp3?+?T cells (Tregs) were determined by flow cytometry in 167 RA patients including 114 GR and 53 PR cases. CD4?+?T cell subsets were also analyzed based on HLA-SE and ACPAs statuses. One hundred nine of 167 patients were positives for HLA-SE, 63.4% for ACPAs, 43.7% for SE/ACPAs and 14.9% were negatives for SE/ACPAs. Higher frequencies of Th2 (P?=?0.001) and Treg cells (P?=?0.03) were found in the patients versus controls. Increased and decreased frequencies of Th2 and Tregs cells were observed in the PR versus GR patients respectively (P?=?0.003 and P?=?0.004). Higher proportions of Th2 cells were observed in the SE⁺RA versus SE^?RA (P?=?0.001), in ACPA⁺RA versus ACPA^?RA (P?=?0.005) and in the SE⁺ACPA⁺RA versus SE^?ACPA^?RA patients (P?=?0.002). Treg cells frequencies decreased in the SE⁺RA versus SE^?RA (P?=?0.03) and in SE⁺ACPA⁺RA versus SE^?ACPA^?RA (P?=?0.02). ACPA⁺GR and SE⁺PR patients showed higher proportions of Th2 cells than ACPA^?GR and SE^?PR patients respectively (P?=?0.02 and P?=?0.01). Analysis of the CD4?+?T cell subsets profiles in conjunction with genetic background and autoantibodies patterns can be useful for precise therapeutic response monitoring in the RA patients.

     

T Cell-Epstein-Barr Virus–Associated Hemophagocytic Lymphohistiocytosis (HLH) Occurs in Non-Asians and Is Associated with a T Cell Activation State that Is Comparable to Primary HLH

Journal of Clinical Immunology - T cell-Epstein-Barr virus–associated hemophagocytic lymphohistiocytosis (T cell-EBV-HLH) is prevalent in East Asia and has poor prognosis. Understanding of...     

Thymic Nurse Cells Support CD4^-CD8^＋ Thymocytes to Differentiate into CD4^＋CD8^＋ Cells

Thymic nurse cells （TNCs） represent a unique microenvironment in the thymus for T cell maturation. In order to investigate the role of thymic nurse cells during T cell differentiation, a TNC clone, RWTE-1, which formed a typical complex with fetal thymocytes in vitro was established from normal Wistar rat. Hanging drop culture method was applied to reveal the interaction between TNCs and thymocytes. Our result revealed that eighty percent of immature CD4^-CD8^＋ cells differentiated into CD4^＋CD8^＋ cells after a 12-hour hanging drop culture with RWTE-1. However, in a 12-hour culture of immature CD4^-CD8^＋ cells with or without RWTE-1 supernatant, only 30% of the cells differentiated into CD4^＋CD8^＋ cells spontaneously. This observation led to the conclusion that RWTE-1 cell has the capacity to facilitate immature CD4^-CD8^＋ thymocytes to differentiate into CD4^＋CD8^＋ T cells by direct interaction.     

Defect of CD8^＋ Memory T Cells Developed in Absence of IL-12 Priming for Secondary Expansion

IL-12 priming plays an important role in stimulation of CD8^＋ effector T cells and development of CD8^＋ memory T （Tm） cells. However, the functional alteration of CD8^＋ Tm cells developed in the absence of IL-12 priming is elusive. In this study, we investigated the capacity of secondary expansion of CD8~ Tm cells developed from transgenic OT I CD8^＋ T cells. The latter cells were in vitro and in vivo stimulated by ovalbumin （OVA）-pulsed dendritic cells [DCovA and （IL-12^-/-）DCovA] derived from wild-type C57BL/6 and IL-12 gene knockout mice, respectively. We demonstrated that IL-12 priming is important not only in CD8^＋ T cell clonal expansion, but also in generation of CD8^＋ Tm cells with the capacity of secondary expansion upon antigen re-encounter. However, IL-12 signaling is not involved in CD8^＋ Tm cell survival and recall responses. Therefore, this study provides useful information for vaccine design and development. Cellular ＆ Molecular Immunology.     

Self-Reactive CD4+ T Cells and B Cells in the Blood in Health and Autoimmune Disease: Increased Frequency of Thyroglobulin-Reactive Cells in Graves’ Disease

The mechanisms underlying activation of potentially self-reactive circulating B cells and T cells remain unclear. We measured the uptake of a self-antigen, thyroglobulin, by antigen presenting cells, and the subsequent proliferation of CD4⁺ T cells and B cells from healthy controls and patients with autoimmune thyroiditis. In Hashimoto's thyroiditis, B cells bound increased amounts of thyroglobulin in a complement- and autoantibody-dependent manner, and the thyroglobulin-elicited proliferation of CD4⁺ T cells and B cells was complement dependent. Increased proportions of Tg-responsive CD4⁺ T cells and B cells were found in patients with Graves’ disease. Notably, both patient groups and healthy controls exhibited higher proliferative responses to thyroglobulin than to a foreign recall antigen, tetanus toxoid. Our results suggest that self-tolerance can be broken by exposure of circulating lymphocytes to high local concentrations of self-antigen, and that complement plays a role in the maintenance of autoimmune processes, at least in Hashimoto's thyroiditis.     

Murine CD5+, CD8+ Normal Fetal Liver Cells Enhance an Immune Response: Benzo(α) Pyrene-Exposed CD5+ Fetal Liver Cells are Inhibitors

The effects of 150 ug benzo(α)pyrene/gm body weight given intraperitoneally to the pregnant mouse at mid-gestation leads to long-lasting (> 18 months post-birth) immune deficiency in the progeny. Although the progeny are immunodeficient their T cell subsets induced marked enhancement and/or inhibition of cell proliferation in an immune response. Earlier we saw a striking increase (up to 7-fold) in CD8⁺ cells in the 18 day gestation liver of benzo(α)pyrene-exposed fetuses. We hypothesized that immune deficiency in carcinogen-exposed progeny could be attributed to an increase in classical CD8⁺ suppressor T-cells. Surprisingly, however, we found that CD8⁺ and CD5⁺ (Lyt 1⁺) cells of normal fetal liver enhance cell proliferation in an immune response. However, liver CD5⁺ cells from benzo(α)pyrene-exposed fetuses led to a dramatic reduction of the enhancing effect. Thus, as a novel finding, it appears that the profile of CD5⁺ cells, under the ontogenic influence of benzo(α)pyrene, transforms from cells that normally augment cell proliferation in an immune response to cells that are inhibitors. On the other hand the functional status of CD8⁺ cells is not affected. This change in physiological status of CD5⁺ cells may have important implications on T and B cell interactions, and the role of CD5⁺cells in T cell receptor signaling.     

Mucosal memory CD8⁺ T cells are selected in the periphery by an MHC class I molecule

The presence of immune memory at pathogen-entry sites is a prerequisite for protection. Nevertheless, the mechanisms that warrant immunity at peripheral interfaces are not understood. Here we show that the nonclassical major histocompatibility complex (MHC) class I molecule thymus leukemia antigen (TL), induced on dendritic cells interacting with CD8αα on activated CD8αβ(+) T cells, mediated affinity-based selection of memory precursor cells. Furthermore, constitutive expression of TL on epithelial cells led to continued selection of mature CD8αβ(+) memory T cells. The memory process driven by TL and CD8αα was essential for the generation of CD8αβ(+) memory T cells in the intestine and the accumulation of highly antigen-sensitive CD8αβ(+) memory T cells that form the first line of defense at the largest entry port for pathogens.     

Trypanosoma cruzi-Induced Activation of Functionally Distinct αβ and γδ CD4? CD8? T Cells in Individuals with Polar Forms of Chagas' Disease

CD4⁻ CD8⁻ (double-negative [DN]) T cells have recently been shown to display important immunological functions in human diseases. They express γδ or αβ T-cell receptors that recognize lipid/glycolipid antigens presented via the nonclassical major histocompatibility complex molecules of the CD1 family. We recently demonstrated that while αβ DN T cells serve primarily to express inflammatory cytokines, γδ DN T cells express mainly interleukin-10 (IL-10) in patients with cutaneous leishmaniasis. We also demonstrated a correlation between DN T cells and the expression of gamma interferon in the acute phase of Trypanosoma cruzi experimental infection. In this work, we sought to investigate whether αβ or γδ DN T cells display distinct immunoregulatory potentials in patients with polar forms of human Chagas'' disease. Our data showed that in vitro infection with T. cruzi leads to expansion of DN T cells in patients with the indeterminate and severe cardiac clinical forms of the disease. However, while αβ DN T cells primarily produce inflammatory cytokines in both forms of the disease, γδ DN T cells display a marked, significant increase in antigen-specific IL-10 expression in indeterminate patients relative to cardiac patients. Finally, higher frequencies of the IL-10-producing γδ DN T cells were correlated with improved clinical measures of cardiac function in the patients, suggesting a protective role for these cells in Chagas'' disease. Taken together, these data show distinct functional characteristics for αβ and γδ DN T cells associated with distinct morbidity rates and clinical forms in human Chagas'' disease.T-cell activation is a key event in the establishment of immune responses directed toward intracellular pathogens. Depending on the functional capacity of the activated T cells, the fate of the infection may take different paths either toward a protective or a pathogenic outcome. While it is important that a strong, activated immune response is elicited early on in the infection in order to eliminate (or control) the pathogen, the further control of this activation is necessary to reestablish homeostasis, avoiding tissue damage (17, 25).One hallmark of most parasitic infections is that the great majority of individuals are able to trigger innate immunity and elicit an activated T-cell response during the acute infection, leading to the control of the parasite and establishment of a chronic infection. Interestingly, while many individuals develop severe forms of parasitic diseases once infection progresses to the chronic phase, most patients develop relatively mild forms, allowing for a host-parasite coexistence. One such example is observed upon human infection with the protozoan parasite Trypanosoma cruzi, which leads to Chagas'' disease. As a result of thousands of years of coevolution between human host and the parasite (6), most infected individuals develop an asymptomatic, or “indeterminate” (I), form of Chagas'' disease. This form is characterized by a lack of clinical signs and symptoms and has been associated predominantly with a modulatory cellular immune response based on cytokine profiles and downregulatory molecule expression (5, 20, 48, 49, 51). Chronic patients may also develop symptomatic clinical forms, mainly with digestive or cardiac alterations. Differential geographical prevalence of Chagas'' disease clinical forms has been reported. In Brazil, 15 to 30% of Chagas'' patients display the cardiac form, which is present in 20 states, while the digestive cases, observed in about 10% of infected individuals, have been reported in four states in the central region of the country (53). The digestive form is frequently found in Chile but is practically absent in Central America (42). These geographical differences might be related, in part, to host genetics and immune responses of local human populations, but it is believed that they are also related to the genetic diversity of T. cruzi strains (11). Different strains of parasite display tropism for different tissues, and, thus, an important factor determining the clinical course of disease might be the specific pool of infecting clones and their specific tropisms (29). However, a possible role for environmental, nutritional, and immunological aspects of the host cannot be discounted. While digestive and cardiac forms present significant morbidity, the cardiac form is the one associated with highest mortality. It is caused by neuronal and cardiomyocyte damage, ultimately resulting in ventricular dilation and subsequent functional heart failure, which can lead to death (44). Cardiac patients display a T-cell-mediated inflammatory response in situ (13, 24, 41), which is responsible for the pathology; this inflammatory profile is also observed in circulating activated T cells found at high frequencies in these patients (2, 16, 19, 32). Although it is clear that a plethora of parasite and host factors influences the clinical outcome of Chagas'' disease, recent studies have suggested that activation of functionally distinct T-cell populations in T. cruzi-infected individuals may be responsible for the establishment of different clinical forms (17, 20). Thus, identifying these populations and the factors responsible for their activation will be critical for driving immune-based interventions to prevent pathology.While the great majority of T cells express either the CD4 or the CD8 molecules, which are important for stabilizing the peptide-major histocompatibility complex (MHC) complex and which favor T-cell activation, a minority population of T cells that do not express CD4 or CD8 molecules has been identified in humans (8, 10, 27, 37). These double-negative (DN) T cells have been shown to be important sources of immunoregulatory cytokines in human leishmaniasis (4), to display modulatory functions (38), but also, under different circumstances, to display cytolytic activity (10, 36). A subpopulation of DN T cells is activated through the engagement of αβ or γδ T-cell receptors (TCRs) in the recognition of nonclassical MHC molecules of the CD1 family, presenting lipid or glycolipid antigens (36). This particular lipid/glycolipid antigenic recognition, as well as the immunoregulatory potential and susceptibility to chronic stimulation of these cells, highlights the important role these cells play in parasitic infections.In our work with Bottrel et al., we determined that DN lymphocytes were the second most prevalent cell type producing gamma interferon (IFN-γ) in human cutaneous leishmaniasis and that this IFN-γ production was seen after short-term cultures with medium alone, as well as after stimulation with soluble Leishmania antigen (SLA) (9). The novel work of Antonelli et al. went on to demonstrate that DN T cells composed of two different cell populations are present in the blood of individuals infected with Leishmania braziliensis and that DN T cells expressing the αβ TCR displayed a profile consistent with activation of leishmanicidal and inflammatory activities (higher IFN-γ and tumor necrosis factor alpha [TNF-α]) while the DN subpopulation expressing γδ TCR had a modulatory potential via higher production of interleukin-10 (IL-10) (4). Interestingly, IFN-γ production has been associated with pathogenic responses in human leishmaniasis in more than one clinical form (3, 7, 22). We recently demonstrated that rats infected with the CL-Brenner clone of T. cruzi displayed a marked increase in the frequency of circulating DN T cells during the acute phase of infection (33). Taken together, these data led to the question of the role that DN T-cell subpopulations play in the clinical dichotomy of chronic human Chagas'' disease.To answer these questions, we investigated the immunoregulatory potential of DN T cells in patients with the two polar forms of Chagas'' disease: indeterminate (I) and dilated cardiac (DC). Our data demonstrated that although no quantitative differences were seen with regard to the nonstimulated frequency of DN αβ and γδ T-cell subpopulations between patients and nonchagasic individuals, in vitro infection with trypomastigote forms of T. cruzi induced a marked increase in the frequency of these cells from chagasic patients. Moreover, the expanded αβ DN T cells displayed a greater inflammatory potential from cardiac patients than from indeterminate patients. This was accompanied by a greater down-modulatory ratio of IL-10 to inflammatory cytokine frequencies by γδ DN T cells from individuals with indeterminate disease, suggesting distinct roles for these cells in modulating the response in chronic Chagas'' disease. Finally, we observed a correlation between higher frequencies of IL-10-producing γδ DN T cells and improved clinical measures of cardiac function, suggesting a protective role for these cells in human Chagas'' disease. These data indicate that functionally distinct DN T cells are present in Chagas'' disease patients and that they are associated with the resulting morbidity of the disease.     

The ex vivo Microenviroments in MLTC of Poorly Immunogenic Tumor Cells Facilitate Polarization of CD4^＋ CD25^＋ Regulatory T Cells

CD4^＋CD25^＋ regulatory T （TR） cells play an important role in maintaining a balanced peripheral immune system. Recent studies have shown that TR cells may also play a key role in suppressing anti-tumor immune response. In order to investigate the tumor immune microenvironment and its influence on TR polarization, poorly immunogenic tumor cell line Ds （C57BL/6, H-2^b）, immunogenic tumor cell lines FBL3 （C57BL/6, H-2^b） and H22 BALB/c, H-2^d） were used to establish the syngeneic/allogeneic, poorly immunogenic/immunogenic mixed lymphocytes-tumor cell culture （MLTC）. Our results revealed that the proportion of CD4^＋CD25^＋ T cells in MLTC of syngeneic primed splenocytes stimulated with D5 tumor cells was higher than that with H22 cells （0.43% vs 0.044%, and the similar results appeared in allogeneic splenocytes stimulated with D5 tumor cells （0.39% vs 0.04%）. The splenocytes stimulated with supernatant from syngeneic MLTC of D5 tumor cells demonstrated higher proportion of CD4^＋CD25^＋ cells than that from allogeneic MLTC of D5 tumor cells, and the splenocytes stimulated with supernatant from syngeneic or allogeneic MLTC of H22 tumor cells generated lower proportion of CD4^＋CD25^＋ T cells than that of D5 tumor cells. The TGF-β1 and Th2-oriented cytokines （IL-4 and IL-10） were dominated in supernatants of syngeneic MLTC of poorly immunogenic tumor cells. Our results provided useful information for studying the mechanisms underlying tumor immune surveillance as well as for the tumor immunotherapy.     

CD4+CD25+CD127low/? T Cells: A More Specific Treg Population in Human Peripheral Blood

The quantitative identification and enrichment of viable regulatory T cells (Treg) requires reliable surface markers that are selectively expressed on Treg. Foxp3 is the accepted marker of nTreg, but it cannot be used to isolate cells for functional studies. In this study, we compared four staining profiles of Treg, including CD4⁺CD25^high T cells, CD4⁺CD39⁺ T cells, CD4⁺CD73⁺ T cells, and CD4⁺CD25⁺CD127^low/? T cells. We found that CD4⁺CD25⁺CD127^low/? T cells expressed the highest level of Foxp3 and had the strongest correlation with CD4⁺CD25⁺Foxp3⁺ T cells, the accepted identifying characteristics for ??real?? nTreg cells. Moreover, functional data showed that CD4⁺CD25⁺CD127^low/? T cells could effectively suppress the proliferation of CD4⁺CD25^? T cells, suggesting that compared with the other three populations, CD4⁺CD25⁺CD127^low/? T cells best fit the definition of naturally occurring regulatory T cells in human peripheral blood. Finally, we showed that CD4⁺CD25⁺CD127^low/? can be used to quantitate Treg cells in individuals with systemic lupus erythematosus supporting the use of CD4⁺CD25⁺CD127^low/? to identify human Treg cells.     

CD8~+T细胞耗竭及靶向CD8~+T细胞免疫治疗的研究进展

T细胞耗竭是慢性感染和肿瘤状态下T细胞发生的一种功能障碍状态。耗竭T细胞效应功能低下,持续高表达抑制性受体,表达转录因子谱与效应和记忆T细胞明显不同。耗竭状态削弱T细胞对感染和肿瘤的有效控制,导致慢性持续感染和肿瘤发生。耗竭T细胞的分化特征、表型标志和功能逆转对临床抗感染和抗肿瘤具有重要的指导意义。靶向耗竭T细胞的免疫治疗已经在实验动物模型和临床治疗研究中获得了较为理想的效果。为此,本文对CD8~+T细胞耗竭特点、影响因素、表型功能与临床治疗等作一综述。