Aire and T cell development

In the thymus, developing T cells that react against self-antigens with high affinity are deleted in the process of negative selection. An essential component of this process is the display of self-antigens, including those whose expression are usually restricted to specific tissues, to developing T cells within the thymus. The Autoimmune Regulator (Aire) gene plays a crucial role in the expression of tissue specific self-antigens within the thymus, and disruption of Aire function results in spontaneous autoimmunity in both humans and mice. Recent advances have been made in our understanding of how Aire influences the expression of thousands of tissue-specific antigens in the thymus. Additional roles of Aire, including roles in chemokine and cytokine expression, have also been revealed. Factors important in the differentiation of Aire-expressing medullary thymic epithelial cells have been defined. Finally, the identity of antigen presenting cells in negative selection, including the role of medullary thymic epithelial cells in displaying tissue specific antigens to T cells, has also been clarified.     

The control of T cell activation vs. tolerance

B7 costimulators and the T cell growth factor IL-2 are important stimuli for the activation of T lymphocytes and the development of effective immune responses. Recent studies show that the same signals promote the development of regulatory T cells or the apoptotic death of activated T cells, and thus, function to terminate immune responses and maintain self-tolerance. The balance between the different outcomes of the same signals may be determined by the magnitude of these signals and the presence or absence of concomitant stimuli, such as those generated during innate immune responses to microbes.     

T cell tolerance

The population of T cells which bears ab receptors is thought to be central to a successful immune response, since it is abbearing cells which stimulate B cells, which give rise to cytotoxic T cells and which secrete many of the essential lymphokines. Self tolerance in this population is therefore absolutely necessary and may even be sufficient to prevent autoimmunity. It is for this reason than immunologists have long tried to understand how tolerance is induced in these cells.     

Control of central and peripheral tolerance by Aire

The negative selection of self-reactive thymocytes depends on the expression of tissue-specific antigens by medullary thymic epithelial cells. The autoimmune regulator (Aire) protein plays an important role in turning on these antigens, and the absence of even one Aire-induced tissue-specific antigen in the thymus can lead to autoimmunity in the antigen-expressing target organ. Recently, Aire protein has been detected in peripheral lymphoid organs, suggesting that peripheral Aire plays a complementary role here. In these peripheral sites, Aire was found to regulate the expression of a group of tissue-specific antigens that is distinct from those expressed in the thymus. Furthermore, transgenic antigen expression in extrathymic Aire-expressing cells (eTACs) can mediate deletional tolerance, but the immunological relevance of Aire-dependent, endogenous tissue-specific antigens remains to be determined.     

Program death-1 regulates peripheral T cell tolerance via an anergy-independent mechanism

Program death-1 (PD-1) has been documented to negatively regulate immune responses. However, the cellular and molecular mechanisms for PD-1-mediated immune suppression have not been fully elucidated. In this study, we show that loss of PD-1 does not lead to defective induction of CD4(+) T cell anergy in vitro and in vivo. Rather, the absence of PD-1 inhibits the development of inducible CD4(+)Foxp3(+) regulatory T cells (iTregs) induced by TGF-β in vitro. In support of this finding, PD-1 deficiency impairs the generation of iTregs in vivo and leads to development of severe T cell-transfer-induced colitis. Mechanistically, defective iTreg generation in the absence of PD-1 was attributed to the heightened phosphorylation of Akt. Therefore, we first demonstrate that PD-1 controls peripheral T cell tolerance via an anergy-independent but iTreg-dependent mechanism.     

Macrophage suppression of T cell activation: a potential mechanism of peripheral tolerance

The mechanisms of induction and maintenance of tolerance in self-reactive T cells in the periphery are poorly understood. Current models assume that successful T cell activation only occurs if ligation of the T cell receptor (signal 1) by antigen presenting cells (APCs) is accompanied by a costimulatory signal (signal 2), and that signal 1 in the absence of signal 2 is either ignored or is tolerizing. However, there is also evidence for the existence of macrophages (M phi) capable of suppressing T cell activation both in vitro and in vivo. The possibility of a more actively induced tolerance exists, in which the M phi itself responds to T cell-mediated signals in a tolerogenic fashion. This would help to resolve the paradox that tissue M phi, which act as scavengers of self-antigen, can also act as professional APCs. The ability of tissue macrophages to actively suppress T cells would further underscore the importance of the innate immune system in regulating adaptive immune responses.     

T cell tolerance and autoimmunity

CD4 T cells are the master controllers of immune responses to protein antigens, and many autoimmune diseases are thought to arise from a breakdown of immunological tolerance in CD4 cells. Peripheral tolerance in CD4 T cells is maintained by several mechanisms, including functional anergy, deletion (death) by apoptosis and suppression by regulatory T lymphocytes (Treg). Using transgenic mouse models, we have explored the roles of these mechanisms in tolerance to cell-associated tissue-restricted self-antigens and secreted systemic self-antigens. Tolerance to a membrane form of the antigen expressed in islet beta cells is maintained by Treg, which block T cell differentiation into pathogenic effectors, and by CTLA-4, which increases the activation threshold of T cells and prevents responses to the self-antigen. A systemically produced soluble form of the antigen induces rapid T cell anergy followed by deletion. The induction of anergy does not require either CTLA-4 or Treg, although in the absence of Treg tolerance can be broken more readily by potent immunogenic signals. Encounter with circulating antigen in T cells induces a state of antigen receptor "desensitization" that is associated with a block in proximal receptor-triggered signals. Thus, different mechanisms play dominant roles in T cell tolerance to different types of self-antigens.     

The role of T cell apoptosis in transplantation tolerance

Rejection of fully MHC-mismatched allografts entails the direct recognition of donor MHC molecules (direct antigen presentation) and the activation of an unusually large mass of alloreactive T cells. There is compelling evidence that apoptotic cell death of activated T cells is a critical initial step in the induction of peripheral allograft tolerance with regimens that are not inherently lymphoablative and that therapies that block T cell activation and T cell apoptosis also block the acquisition of tolerance. Thus, T cell apoptosis may play an important role in reducing the size of cytopathic T cell clones and this process may also promote the development and expansion of immune regulatory cells that are essential in the maintenance of allograft tolerance.     

T cell tolerance and autoimmunity

A functional immune system requires a T cell repertoire that is extremely diverse so as to allow for the elimination of all possible pathogens. However, the production of an immense T cell repertoire also increases the likelihood of generating autoreactive T cells. The immune system must therefore also incorporate a means of silencing or eliminating autoreactive T cells, while minimally sacrificing T cell diversity. The induction and maintenance of T cell unresponsiveness to self antigens is thus defined as T cell tolerance. This review provides an overview of the T cell tolerance mechanisms invoked in the thymus and in the periphery to prevent the induction of autoimmunity. Factors that can influence the induction of tolerance and autoimmunity are also discussed.     

Aire regulates negative selection of organ-specific T cells

Autoimmune polyendocrinopathy syndrome type 1 is a recessive Mendelian disorder resulting from mutations in a novel gene, AIRE, and is characterized by a spectrum of organ-specific autoimmune diseases. It is not known what tolerance mechanisms are defective as a result of AIRE mutation. By tracing the fate of autoreactive CD4+ T cells with high affinity for a pancreatic antigen in transgenic mice with an Aire mutation, we show here that Aire deficiency causes almost complete failure to delete the organ-specific cells in the thymus. These results indicate that autoimmune polyendocrinopathy syndrome 1 is caused by failure of a specialized mechanism for deleting forbidden T cell clones, establishing a central role for this tolerance mechanism.     

对ANT合成肽诱导的自身免疫性心肌病传染性耐受的小鼠T细胞信号机制分析

目的：通过对T细胞信号分子和CIM5的表达分析探讨T细胞信号转导在自身免疫性心肌病小鼠传染性耐受中的作用。方法：用含有人线粒体腺苷酸转位酶（ANT）多肽的免疫液多次免疫BALB／c小鼠得到心肌病组（n=6），单抗组（n=6）小鼠在给予ADP／ATP肽免疫的第0、1和2天，同时接受尾静脉注射400μg抗L3T4单抗；第180天时，将单抗组小鼠的脾淋巴细胞取出转输到正常小鼠体内（转输组，n=6），此小鼠亦同时给予多肽免疫，方法同心肌病组。正常对照组（n=6），以不含多肽的盐水免疫小鼠，时间和剂量同心肌病组。以实时荧光定量PCR法检测各组小鼠T细胞中的信号分子（p561ck、p59fyn和zap-70）mRNA的表达；免疫组化法观察其T细胞表面CD45的表达；流式细胞术检测其n细胞内细胞因子IFN-γ和IL-4的含量。结果：过继转输组小鼠T细胞内三个信号分子的mRNA表达均受到抑制，T细胞表面CIM5的表达强度亦明显低于心肌病组；通过流式细胞术检测到的IFN-γ和IL-4的含量在转输组亦明显降低。结论：T细胞信号机制在自身免疫性心肌病的发病机制中起重要作用，通过对T细胞信号通路的干预，可能阻止实验鼠自身免疫性心肌病的发生。     

The control of immunity and tolerance by dendritic cell

Dendritic cells (DCs) are best known for their roles in host resistance and immunogenicity. DCs provide a direct link between innate and adaptive immunity. After antigen capture and processing, DCs control the differentiation and polarization of T cells. However, there is a danger during the antigen presentation because, at the same time DCs are capturing microbial antigens and also dying self cells and environmental proteins, to which the immune system must not respond. There is good evidence that immature DCs, in the absence of infection and inflammation, induce immunological tolerance to innocuous self antigens, avoiding then a non-appropriate response to harmless antigens that may be presented subsequently when infection strikes.     

水仙环素抑制T细胞增殖的作用机制

目的 探究水仙环素抑制T细胞增殖与功能的作用机制.方法 密度梯度离心法及免疫磁珠法纯化人外周血T细胞,anti-CD3/anti-CD28抗体活化T细胞.使用流式细胞仪检测细胞增殖、CD25的表达、细胞毒性及细胞周期;酶联免疫吸附试验检测细胞因子IL-2、IL-6、IL-17及IFN-γ的分泌水平.结果 水仙环素抑制a...     

DCs and peripheral T cell tolerance

Tolerance is a state in which the immune system as a whole fails to make an active response to antigen. Three mutually exclusive mechanisms appear to account for the fate of antigen-specific peripheral T cells within a tolerant animal: maintenance of naive status, deletion after responding to antigen, and long term survival after responding to antigen, a mechanism that should probably be considered part of the spectrum of memory responses. The types and functional status of the DCs that present antigen in each case remain controversial. This review will summarize the indirect evidence that underlies some of the hypotheses that account for peripheral T cell tolerance.