Human CD8+CXCR3+ T cells have the same function as murine CD8+CD122+ Treg

The importance of CD8⁺CD122⁺ Treg in the maintenance of immune homeostasis has been previously demonstrated in mice. Because the expression pattern of CD8 and CD122 in humans is different from that in mice, human CD8⁺ Treg that correspond to the murine CD8⁺CD122⁺ Treg have not been identified. In this study, we performed DNA microarray analyses to compare the gene expression profiles of CD8⁺CD122⁺ cells and CD8⁺CD122^? cells in mice and found that CXCR3 was preferentially expressed in CD8⁺CD122⁺ cells. When we analyzed the expression of CD122 and CXCR3 in murine CD8⁺ cells, we observed a definite population of CD122⁺CXCR3⁺ cells. CD8⁺CXCR3⁺ cells in mice showed similar regulatory activities to CD8⁺CD122⁺ cells by in vivo and in vitro assays. While CD8⁺CD122⁺CXCR3⁺ cells are present in mice, CD8⁺CXCR3⁺ cells, but not CD8⁺CD122⁺ cells, are present in humans. In the in vitro assay, human CD8⁺CXCR3⁺ cells showed the regulatory activity of producing IL‐10 and suppressing IFN‐γ production from CD8⁺CXCR3^? cells. These results suggest that human CD8⁺CXCR3⁺ T cells are the counterparts of murine CD8⁺CD122⁺ Treg.     

Differential roles for CXCR3 in CD4+ and CD8+ T cell trafficking following viral infection of the CNS

Lymphocyte infiltration into the central nervous system (CNS) following viral infection represents an important component of host defense and is required for control of viral replication. However, the mechanisms governing inflammation in response to viral infection of the CNS are not well understood. Following intracranial (i.c.) infection of susceptible mice with mouse hepatitis virus (MHV), mice develop an acute encephalomyelitis followed by a chronic demyelinating disease. The CXC chemokine ligand 10 (CXCL10) is expressed following MHV infection and signals T cells to migrate into the CNS. The functional contribution of the CXCL10 receptor CXCR3 in host defense and disease in response to MHV infection was evaluated. The majority of CD4+ and CD8+ T cells infiltrating the CNS following MHV infection express CXCR3. Administration of anti-CXCR3 antibody reduced CD4+ T cell infiltration (p相似文献   

Role of co-stimulation in CD8+ T cell activation

The two-signal model states that activation of naive T cells requires a signal 1 stimulus through the TCR and a co-stimulatory signal 2. By contrast, signal 1 alone is sufficient for pre-activated T cells. Recently, however, it has been shown that under certain conditions T cells can bypass the requirement for co-stimulation. For example, CD28- deficient mice, when immunized with lymphocytic choriomeningitis virus, mount a vigorous cytotoxic T lymphocyte response and clear the virus. As a continuous effort to unravel the mechanisms of T cell activation, we previously reported activation of hybridoma T cells by recombinant single-chain MHC molecules in the absence of antigen-presenting cells. In such reconstitution experiments, since the signals delivered to the T cells are well controlled, the contribution of any known or unknown signals can be ruled out. In the present study, we analyzed the requirements for activation of naive T cells by using splenocytes from TCR transgenic mice as a source of responding cells. We observed that naive CD8+ T cells are fully activated by signal 1 alone, but that co- stimulation lowers their activation threshold. Previously activated T cells are fully responsive, even when the first stimulation was performed in the absence of co-stimulation. They display a low activation threshold and are insensitive to co-stimulation. The physiological relevance of this finding and its consequences for immunotherapy as well as for our understanding of self-tolerance are discussed.      

Dynamic imaging of chemokine-dependent CD8+ T cell help for CD8+ T cell responses

Naive T lymphocytes move efficiently in lymphoid tissues while scanning dendritic cells in search of cognate complexes of peptide in major histocompatibility molecules. However, T cell migration ceases after recognition of cognate antigen. We show here that during the initiation of antigen-specific CD8(+) T cell responses, naive CD8(+) polyclonal T cells 'preferentially' interacted in an antigen-independent way with mature dendritic cells competent to present antigen to antigen-specific CD8(+) T cells. These antigen-independent interactions required expression of the chemokine receptor CCR5 on polyclonal T cells and increased the efficiency of the induction of naive, low-precursor-frequency CD8(+) T cell responses. Thus, antigen-specific CD8(+) T cells favor the priming of naive CD8(+) T cells by promoting the CCR5-dependent recruitment of polyclonal CD8(+) T cells to mature dendritic cells.     

IL-21R expression on CD8+ T cells promotes CD8+ T cell activation in coxsackievirus B3 induced myocarditis

IL-21 is a multi-functional cytokine which can promote survival, proliferation and activation of T and B lymphocytes including CD8 T cells. Previous studies have shown that autoimmune CD8+ T cells are the primary pathogenic effector cell in coxsackievirus B3 (CVB3) induced myocarditis in C57Bl/6 mice. To evaluate the role of IL-21 in promoting CD8+ T cell mediated cardiac injury in myocarditis, C57Bl/6 and IL-21RKO mice were infected with CVB3. IL-21RKO mice developed significantly less myocarditis than C57Bl/6 animals although cardiac virus titers were equivalent between the mouse strains. Numbers of CD8+IFNγ+ cells were decreased in IL-21RKO mice but numbers of either CD4+IFNγ+ or CD4+IL-4+ cells were not significantly different from C57Bl/6 animals indicating a selective effect of IL-21 signaling on the CD8+ T cell response. To confirm that IL-21 signaling exclusively functions at the level of the CD8+ T cell in CVB3 induced myocarditis, purified CD8+ cells were isolated from either C57Bl/6 or IL-21RKO donors and adoptively transferred into CD8KO recipients prior to CVB3 infection. CD8KO recipients given either C57Bl/6 or IL-21RKO CD8+ cells showed equivalent reconstitution of the CD8+ cells in the spleen but the recipients given C57Bl/6 CD8+ cells showed significantly greater myocarditis than recipients of IL-21RKO CD8+ cells. These data demonstrate that IL-21 signaling directly in the CD8+ cell population is required for CVB3-induced myocarditis.     

CD3+ CD8+ T cell lymphocytosis masking B cell leukaemia.

A patient with CD3, CD8 positive lymphocytosis presented with features consistent with T cell chronic lymphocytic leukaemia/proliferations of large granular lymphocytes. The marrow and blood lymphoid populations (19.4 x 10(9)/l) contained more than 80% CD3 and CD8 positive cells with no evidence of a monotypic B cell population. A biopsy specimen of a vasculitic rash showed a diffuse infiltrate of CD3, CD8 positive cells into the upper dermis, consistent with T cell lymphocytic disease. After follow up for two years without treatment the blood lymphocyte count was 53 x 10(9)/l and was composed of cytologically small lymphocytes. A monoclonal SIg M D k lymphoid population (more than 90%) was demonstrable in sample blood and marrow aspirate. Gene rearrangement studies carried out on DNA extracted from peripheral blood lymphocytes at presentation and at two year follow up exhibited JH and Ck immunoglobulin gene rearrangement but no rearrangement of T cell receptor TcR gamma and beta genes. It is thought that this is the first well documented case of an aggressive CD8 positive lymphocytosis preceding, or in response to, an underlying B cell neoplasm.     

CD8+ T 细胞活化与分化的分子机制

CD8+ T 细胞识别由MHC玉分子递呈的抗原肽,由于大多数有核细胞都表达MHCⅠ分子,因此CD8+ T 细胞在清除被病毒、胞内菌、寄生虫等感染的细胞或突变的肿瘤细胞中发挥着重要作用。识别病原微生物等抗原后,CD8+ T 细胞活化并分化形成多种类型的效应和记忆细胞,不仅能及时清除被感染的细胞,也能形成长期保护。各亚群CD8+ T 细胞的表面分子、功能和定位不同,细胞存活的时间、再次感染时的增殖能力和效应功能也有所差别。本文主要讨论CD8+ T 细胞如何受到多条信号通路和转录因子调控,活化和分化成不同类型的效应和记忆细胞,并对临床应用T 细胞抵御肿瘤和病原微生物的进展作一简单概述。     

The CC chemokine ligand 3 regulates CD11c+CD11b+CD8alpha- dendritic cell maturation and activation following viral infection of the central nervous system: implications for a role in T cell activation

The role of CC chemokine ligand 3 (CCL3) in activation of dendritic cells (DCs) following mouse hepatitis virus (MHV) infection of the central nervous system (CNS) was examined. The results indicate that CCL3 participates in an effective host response to MHV infection by contributing to CD11c+CD11b+CD8alpha- DC maturation, activation, and migration to cervical lymph nodes (CLN). Diminished CD8alpha- DC activation correlated with reduced IFN-gamma expression by virus-specific T cells accompanied by increased IL-10 production suggesting that CCL3 contributes to an effective host response to viral infection by enhancing the T cell activation potential of DC.     

Requirement for both the CD3/T cell receptor complex and the CD2/lymphocyte function-associated antigen-3 adhesion system in monocyte-independent T cell activation by oxidized erythrocytes

Recent reports have shown that human T lymphocytes can be activated in vitro by desialyzed oxidized erythrocytes (DOE) in a monocyte-independent fashion. These findings suggest that, in addition to providing the activating stimulus, DOE may also fulfill accessory cell roles normally supplied by monocytes in T cell activation. DOE may thus be a useful substitute for antigen-presenting accessory cells in studies of T cell activation. This report describes experiments conducted to determine if T cell activation by DOE involves cell surface structures known to play a role in antigen-induced T cell activation. T cell stimulation by DOE was blocked by anti-CD3 monoclonal antibody, suggesting that perturbation of the CD3/T cell antigen receptor complex on T cells is required for activation. Activation was also blocked by anti-CD2 monoclonal antibody, indicating involvement of the CD2/LFA-3 adhesion system. Since DOE and monocytes both express LFA-3, the role of LFA-3 on DOE in T cell activation was assessed. DOE pretreated with anti-LFA-3 monoclonal antibody induced markedly lower levels of T cell proliferation. As further evidence for LFA-3 involvement, DOE prepared from 5 patients with paroxysmal nocturnal hemoglobinuria (PNH), known to exhibit deficient LFA-3 expression, were also deficient in T-cell stimulatory activity. These findings illustrate that T cell activation by DOE requires many of the surface structures involved in activation by antigen-bearing accessory cells, and may thus serve as a useful model for studies of T cell activation.     

Minimal activation of memory CD8+ T cell by tissue-derived dendritic cells favors the stimulation of naive CD8+ T cells

Of the many dendritic cell (DC) subsets, DCs expressing the monomorphic coreceptor CD8 alpha-chain (CD8alpha) are localized permanently in lymphoid organs, whereas 'tissue-derived DCs' remain in nonlymphoid tissues until they 'capture' antigen and then move to local lymph nodes. Here we show that after lung infection, both naive and memory CD8+ 'killer' T cells responded to influenza virus antigens presented by lymph node-resident CD8alpha+ DCs, but only naive cells responded to antigens presented by lung-derived DCs. This difference provides a mechanism for priming naive T cell responses in conditions in which robust memory predominates. Our findings have implications for immunity to pathogens that can mutate their T cell epitopes, such as influenza virus and human immunodeficiency virus, and challenge the long-held view that memory T cells have less-stringent requirements for activation than naive T cells have.     

Requirements for activation of CD8+Murine T cells

Cytolytic effector function fails to develop if proliferation of allospecific cytolytic T lymphocyte precursors is inhibited, but the requirements for generation of cytolytic activity have not been fully defined. In contrast, the cytolytic effector function of cytolytic T lymphocyte clones does not change during the cell cycle, and the level of cytolytic activity is independent of cellular proliferation. The requirement for proliferation by primary responding populations may reflect the need for clonal expansion of a few inherently cytolytic effector cells in order to reach a threshold number which can readily be detected in conventional cytolytic assays. Alternatively, proliferation may be required for cytolytic T lymphocyte precursors to differentiate into mature, functional cytolytic cells. Using CD8+T cells which express an antigen-specific transgenic α/β T cell receptor, we have studied the requirements for acquisition of cytolytic capacity. Stimulation of the T cell receptor alone appears to be sufficient to render naive, CD8+ transgenic T cells sensitive to the growth effects of interleukin-2 (IL-2), and in some circumstances to interleukin-4 (IL-4), but not to induce either lymphokine production or cytolytic activity. Costimulatory molecules expressed by allogenic stimulating cells appear to be required for lymphokine production, and CD8+ transgenic T cells initially appear to secrete only IL-2 and interferon-γ. Stimulation of the T cell receptor of naive, CD8+ transgenic T cells appears to induce cytolytic activity only if cell proliferation occurs, either in response to IL-2 produced by the stimulated cells themselves when costimulatory molecules are present, or to IL-2 or IL-4 from exogenous sources if costimulatory molecules are absent.     

CD3+CD4-CD8- alphabeta-TCR+ T cell as immune regulatory cell

Down-regulation of immune responses by regulatory T cells is one of the major mechanisms involved in the induction of tolerance to self- and alloantigens as demonstrated in a number of models of transplantation and autoimmunity. It is clear that regulatory T cells consist of different subsets. Recently a novel subset of antigen-specific alphabeta-TCR+ CD4-CD8- (double negative, DN) regulatory T cells has been found to be able to inhibit the function of the CD8+ T cells carrying the same T cell receptor specificity and prevent the rejection of skin allografts. Identification of the DN regulatory T cells and their novel mechanism of suppression can help us to understand how donor-specific transplantation tolerance can be achieved and to explain how tolerance to self-antigens can be maintained in the periphery.     

Inflaming the CD8+ T cell response

Although inflammatory cytokines induced by infection or vaccination with adjuvants have long been known to stimulate optimal antigen-presenting cell function, recent evidence indicates that some inflammatory cytokines also act directly on the responding T cells to control their response to infection. Here, we review the evidence that specific inflammatory cytokines act to control the magnitude of expansion, the degree of contraction, and the rate of memory cell development. These data may suggest new strategies for manipulating vaccine efficacy in the quest to protect against pathogenic microbes.     

Functional and phenotypic analysis of human memory CD8+ T cells expressing CXCR3

Several chemokine receptors play an important role in the migration of na?ve, memory, and effector T cells. Flow cytometric analyses showed that human CD8+ T cells with na?ve (CD27+ CD28+ CD45RA+) or memory (CD27+ CD28+/- CD45RA+) phenotypes included a population expressing a high level of CXC chemokine receptor 3 (CXCR3high) and one expressing a low level of it (CXCR3low), but those with the effector phenotype (CD27- CD28- CD45RA+/-) included a population that did not express CXCR3 (CXCR3-) and a CXCR3low population. This relation between the expression level of CXCR3 and memory/effector phenotypes also applied to Epstein-Barr virus- or human cytomegalovirus-specific CD8+ T cells. CXCR3high cells were found predominantly in CC chemokine receptor 7 (CCR7)+ CCR5- and CCR7- CCR5- subsets of CD8+ T cells with the CD27+ CD28+ CD45RA- memory phenotype, suggesting that they are memory cells with intermediate differentiation. Indeed, CXCR3high CD27+ CD28+ CD45RA- CD8+ T cells had the ability to produce interleukin-2 and interferon-gamma. These results together indicate that the expression of CXCR3 is up-regulated on intermediately differentiated memory CD8+ T cells. CXCR3high CD8+ T cells had a greater ability to migrate in response to CXCR3 ligands than CXCR3low ones. As CXCR3high memory CD8+ T cells do not express CCR5, high expression of CXCR3 on these memory CD8+ T cells might play an important role in the migration of these cells to inflammatory sites and in their differentiation.     

Notch signalling regulates cytokine production by CD8+ and CD4+ T cells

The Notch signalling pathway regulates several aspects of cellular differentiation such as T lineage commitment and effector functions on peripheral T cells; however, there is limited information regarding Notch receptor expression on different T cell subsets and the putative role of the different receptors on T cell effector function. Here, we studied the protein expression of Notch receptors on murine T cells in vitro and in vivo and analysed the role of the Notch pathway in cytokine production by CD4+ and CD8+ T cells. We found that resting CD4+ and CD8+ T cells do not express Notch receptors, but they upregulate Notch 1 and Notch 2 shortly after in vitro and in vivo activation. Using a γ-secretase inhibitor, which blocks Notch signalling through all Notch receptors, we demonstrated that the Notch pathway regulates IL-10 production by CD4+ T cells and IFN-γ and IL-17 production by CD8+ T cells. These results suggest that Notch 1 and 2 are expressed by CD4+ and CD8+ T cells and represent the putative Notch receptors that regulate effector functions and cytokine production by these cells.     

In vitro model for the activation of CD4 and CD8 T cell receptors

Previously, most models that sought to explain the misregulation of immune cell function assumed molecular similarities between the disease-causing pathogens and the host's proteins. In recent time several different models have been proposed and in this study, these concepts are compared to a new hypothesis proposing another explanation for this immune dysregulation: the possibility that the mislocalization of proteins may be responsible for autoimmune activity. Based on this hypothesis, proteins are recognized as self or non-self depending on where they appear in sufficiently high concentrations. To examine this new idea, the intracellular human proteins β-actin, GAPDH, and hemoglobin as well as the extracellular human proteins insulin and albumin, were added to human whole blood samples. After an incubation period, the activation of whole-blood T lymphocytes in the samples was measured. The observed activation pattern of the T lymphocytes fit well with the proposed hypothesis. Therefore, these data suggest that protein mislocalization and/or errors within protein trafficking might be important in the development of autoimmune diseases.     

CD4+ T cell help improves CD8+ T cell memory by retained CD27 expression

CD4+ T cell help during the priming of CD8+ T lymphocytes imprints the capacity for optimal secondary expansion upon re-encounter with antigen. Helped memory CD8+ T cells rapidly expand in response to a secondary antigen exposure, even in the absence of T cell help and, are most efficient in protection against a re-infection. In contrast, helpless memory CTL can mediate effector function, but secondary expansion is reduced. How CD4+ T cells instruct CD8+ memory T cells during priming to undergo efficient secondary expansion has not been resolved in detail. Here, we show that memory CTL after infection with lymphocytic choriomeningitis virus are CD27(high) whereas memory CTL primed in the absence of CD4+ T cell have a reduced expression of CD27. Helpless memory CTL produced low amounts of IL-2 and did not efficiently expand after restimulation with peptide in vitro. Blocking experiments with monoclonal antibodies and the use of CD27(-/-) memory CTL revealed that CD27 ligation during restimulation increased autocrine IL-2 production and secondary expansion. Therefore, regulating CD27 expression on memory CTL is a novel mechanism how CD4+ T cells control CTL memory.