Origin

The origin and persistence of autoreactive T cells is most readily understood from a consideration of the requirements for T cell maturation. The mature peripheral T cell population is restricted to recognize foreign antigens in association with only those major histocompatibility complex (MHC)-encoded molecules expressed in the thymic differentiation environment. Since foreign antigens are not, in general, present in that environment, this clearly means that at an early stage of differentiation T cell precursors are self reactive. It is presumed that some process of negative selection prevents seeding any very high affinity self reactive clones in the mature population. Nevertheless, antigen-specific, MHC-restricted peripheral T cells must derive from thymic precursors that express a functional affinity for self MHC, possibly in association with other self molecules. The basis for this transition from an autoreactive thymic precursor to an antigen-dependent, MHC-restricted peripheral T cell is not understood. Present evidence suggests that this transition cannot be explained by somatic mutation of rearranged T cell receptor genes. It appears, therefore, that T cell maturation must be accompanied by physiological changes that modulate T cell activation signals or activation thresholds such that self MHC recognition does not, in general, suffice to induce clonal expansion of resting peripheral T cells. Such changes could reflect properties of mature T cells relative to thymic precursors as well as properties of the stimulatory environment in secondary lymphoid tissues relative to the thymus. The nature of these physiological changes is not known and their stability cannot be predicted. A considerable body of evidence suggests, however, that some mature T cells either have retained or reacquired the ability to be stimulated by self MHC in the absence of foreign antigens.

Autoreactive T cells and T cell lines derived from normal individuals have been independently described in many laboratories. Such T cells are activated in the absence of any identifiable foreign antigen by class II MHC syngeneic but not MHC allogeneic stimulators. In particular, autoreactive responses have been demonstrated in the absence of xenogeneic serum components. It has been suggested that such T cells manifest the autoreactive specificity that was the basis for positive selection in the thymus. This is supported by evidence that autoreactive T cells can derive from antigen-specific precursors. It has been shown that, under well-defined conditions, the specificity of autoreactive T cell clones selected from antigen-primed populations reflects the predominant MHC restriction specificity of T cells specific for the immunogen. Thus, I-E subregion specific autoreactive T cells are detected at a much higher frequency in populations primed with a foreign antigen whose presentation is I-E-rcstricted than in populations primed with antigen whose presentation is predominantly I-A-restricted. A striking confirmation and extension of these observations has been noted in the analysis of T cell receptor gene expression in autoreactive T cell clones selected from pigeon cytochrome c-stimulated populations. The diversity of germ-line T cell receptor variable region genes expressed in the pigeon cytochrome c-specific T cell repertoire is relatively limited. It has been observed that autoreactive T cells also arise in pigeon cytochrome c-stimulated T cell lines and that the same T cell receptor genes predominate in these autoreactive T cells as in the antigen-specific T cells. These results strongly support the conclusion that autoreactive T cells can derive from antigen-stimulated precursors.

Such 'normal' autoreactivity may represent a particular physiological state that recapitulates the conditions of thymic selection and is induced in many antigen-specific, MHC-restricted peripheral T cells as a result of normal antigen-dependent activation. In keeping with the suggested physiological difference, there is evidence that autoreactive T cells have unique activation requirements distinct from the activation requirements of antigen-specific, MHC-restricted T cells. In particular, it has been shown that autoreactive T cells are more dependent on interleukin 1 (IL-1) and on signals transduced through recognition of MHC class II on the stimulator cell than are antigen-specific T cells.

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