摘要:

The immune system is constructed to tolerate self antigens but give vigorous responses to foreign antigens. How this state of self/nonself discrimination is maintained is controversial. In the case of T cells, many self antigens are transported to the thymus via the bloodstream and induce tolerance (clonal deletion) of self-reactive thymocytesin situ.Although such central tolerance in the thymus is well documented, it is often argued that full induction of tolerance requires peripheral mechanisms such as suppression or induction of anergy. This article proposes that steady-state tolerance of T cells to self components is due solely to central tolerance to circulating self antigens combined with sequestration of tissue-specific antigens. Backup mechanisms for tolerance do exist but such immunoregulation only operates when self tolerance breaks. This scheme allows the immune system to give unrestricted primary responses to foreign antigens.

ISSN:0883-0185    

DOI:10.3109/08830189509061740

出版商:Taylor&Francis    

年代:1995

数据来源: Taylor

摘要:

There are now numerous reports documenting the deletion of mature peripheral specific T cells following massive antigenic stimulation. Such a phenomenon can be regarded as a homeostatic mechanism to prevent unrestricted growth of antigen-activated clones and to safeguard against autoimmunity. Some of the reports examining this issue are summarized in this review and the role of the liver in tolerance and autoimmunity is discussed based on recent work performed with transgenic mice.

ISSN:0883-0185    

DOI:10.3109/08830189509061741

出版商:Taylor&Francis    

年代:1995

数据来源: Taylor

摘要:

Antigen-induced T cell death is an important regulatory mechanism in the peripheral immune system. Evidence suggests that this process depends on T cell growth-inducing lymphokines such as IL-2 and occurs in proportion to the degree of T cell receptor occupancy. Strong T cell receptor stimulation leads to the synthesis of death molecules such as Fas ligand and tumor necrosis factor that cause T cell suicide. We propose that T cell death under these circumstances is the culmination of a feedback control mechanism termed propriocidal regulation or autocrine feedback death that regulates the expansion of specific T cell clones under conditions of high lympho-kine and antigen load. In a quasi-stochastic system such as the antigen receptor repertoire, feedback information may be essential for the appropriate regulation of peripheral immune responses. Our understanding of this feedback mechanism affords a means to manipulate antigen-specific T cell deathin vivo.The application of this approach to the therapy of T cell-medicated immunological diseases is discussed.

ISSN:0883-0185    

DOI:10.3109/08830189509061742

出版商:Taylor&Francis    

年代:1995

数据来源: Taylor

摘要:

The two signal model of T cell activation predicts that a second costimulatory signal provided by antigen presenting cells (APC) is required in conjunction with the antigenic signal to trigger T cell activation. Considerable evidence indicates that indeed, T cell activation requires such a costimulatory signal which results, at least in part, from the interaction of CD28 with its ligands B7 expressed on all antigen-presenting cells (APC). The second prediction of the two signal model is that T cell receptor engagement in the absence of such a costimulatory signal would lead to specific inactivation of antigen reactive cells. Thus, tissue cells that do not express costimulatory signals would not trigger T cell activation but rather lead to specific inactivation of auto-reactive T cells. By such a model, tolerance to peripheral antigens would be permanently re-established.We review here the evidence suggesting that the CD28-B7 costimulatory pathway might play an important role in T cell tolerance and in the development of autoimmune responses.

ISSN:0883-0185    

DOI:10.3109/08830189509061743

出版商:Taylor&Francis    

年代:1995

数据来源: Taylor

摘要:

While the thymus may be effective in inducing tolerance to lymphoid associated antigens, it is not as efficient in deleting T cells reactive to peripheral tissue specific antigens. Therefore, to maintain self tolerance to peripheral tissues, post-thymic mechanisms must be invoked. One important way to prevent autoimmune pathology mediated by autoreactive CD4 T cells is the diversion of clones to regulatory Th2 effector cells. However, many different factors contributein vivoto the decision of stimulated CD4 T cells to develop into Th1 versus Th2 cells. For example, T cell signaling pathways may influence the types of cytokines produced by naive T cells, and studies have provided evidence for a genetic polymorphism among common mouse strains that can significantly influence the early cytokine production in stimulated naive CD4 T cells. The allele carried by the BALB/c strain promotes IL-4 production, and consequently provides resistance to autoimmune diabetes in our transgenic mouse model. In addition, antigen presenting cells can influence the development of stimulated CD4 T cells in part through the production of cytokines such as IL-12. The absorption of IL-12in vivocan permit the expansion of Th2 type effector cells, and this phenomenon will also protect mice from autoimmunity. Finally, the relative potency of various class II positive antigen presenting cell types can influence the development of autoreactive T cells, with dendritic cells apparently being the strongest stimulator of Th1 responses. Consistent with this notion, a relB knockout mouse, which is missing dendritic cells, appears to drive Th2 development even in response to viral infection. In sum, these various influences over the Th1/Th2 decisionin vivomay provide new targets for immunotherapy of autoimmune diseases.

ISSN:0883-0185    

DOI:10.3109/08830189509061744

出版商:Taylor&Francis    

年代:1995

数据来源: Taylor

ISSN:0883-0185    

DOI:10.3109/08830189509061739

出版商:Taylor&Francis    

年代:1995

数据来源: Taylor