Achieving antigen-specific immune regulation (original) (raw)

One possible explanation for the occurrence of autoimmune responses is that the T cell repertoire of patients with diabetes includes autoreactive clones that have escaped thymic deletion to islet proteins, including proinsulin. These proteins, generally thought to be islet specific, are also expressed in the thymus. In fact, one report has described higher expression of insulin mRNA in the thymuses of individuals with insulin variable numbers of tandem repeats associated with protection from diabetes (7). These investigators postulate that higher insulin expression in the thymuses of disease-protected subjects may lead to deletion of autoreactive cells.

However, animal models, in which antigen expression is limited to islet cells, have not supported the concept that the escape of “forbidden clones” alone is sufficient to account for autoimmunity (8). Peripheral mechanisms of T cell activation and regulation control autoimmune responses even in the presence of autoreactive T cells.

Much interest has focused on the phenotype of the T cell response that differentiates after activation, as most autoimmune T cell responses are polarized toward a Th1 phenotype, and Th2 responses are thought to be protective (9). This explanation alone does not account for protection from autoimmunity, because in certain situations, when transferred into an immune-deficient mouse, Th2 cells thought to be protective can cause diabetes (10). In addition, protection requires more than a single Th2 cell; it takes a “village.” When the T cell repertoire has been restricted experimentally, even conditions that favor Th2 development can result in disease (11). These findings and others from several animal models of T1DM suggest that the differentiation of a large number of cells that are recruited to an inflammatory response toward a nonpathogenic phenotype is an effective means of controlling autoimmune responses. In experimental systems, controlling the phenotype of the effector cell itself may not be sufficient to regulate the response.

A more potent means of regulating immune responses involving regulatory T cells has been studied intensively (12, 13). Certain regulatory T cells, such as CD4+CD25+ T cells, are present constitutively, whereas others, including a subpopulation of regulatory T cells (Tr1 cells) that produce IL-10 and IFN-γ, as well as subpopulations of CD8+ cells including those reactive with class Ib MHC molecules and others that express low levels of CD28, are induced following cell activation (14, 15). These cells appear to be very potent in their actions. Ratios of regulatory:effector CD4+ T cells as low as 1:20 have been found to inhibit antigen-specific responses.