Ontogeny of MHC-linked, T cell-mediated suppression is regulated by the T cell genotype

Regulation of T cell effector functions by major histocompatibility complex (MHC) gene products has been extensively researched. Investigations in this area have established several important concepts of immunobiology. First, genes within the I-region of the MHC profoundly affect development of immune responses through their effects on cell-cell interactions. In the course of analyzing antigen-induced T cell activation, investigators identified specific Ir-genes by demonstrating that certain strains of mice were unable to develop immunity to defined antigens. It is now accepted that immune response defects in murine species are potentiated by cell surface molecules encoded within the I-subregion of the MHC, called Ia. Those molecules coded within the I-A subregion have the potential to be expressed by many different cell types. Second, induction of helper T cell effector function requires recognition of antigen in association with I-region encoded, cell surface molecules. For example, only a single structural combination of antigenic determinant and Ia molecule can deliver the inductive signal(s) to potential helper T cells. This fundamental aspect of helper T cell activation, now documented in numerous experimental systems, is referred to as MHC- or I-region restricted, antigen recognition. MHC-restriction is a characteristic of T cells mediating delayed-type hypersensitivity, help, and cytotoxicity. Third, several lines of evidence have established that T cell recognition of self-MHC molecules is a modifiable phenotype; conferred by a receptor having both variable and constant regions and not encoded by genes in the MHC. The development of both thymic grafted homozygous nu/nu mice and irradiation-induced bone marrow chimeras as experimental models resulted in a better understanding of the mechanism of MHC-restricted, antigen recognition. It was observed that expression of MHC gene products by the host is sufficient to select a new immune response phenotype for cellular interactions. The selection process takes place during T cell maturation, in the absence of antigen and under the dominant influence of the thymus, even though there is ample evidence for selective pressure in the extrathymic environment. For example, the self-MHC recognition repertoire of T cells in P----F1 chimeras undergoes an initial expansion which results in an F1 immune response phenotype. This expansion is followed by an apparent contraction back to the immune response phenotype of the parental donor. The contraction is time dependent and reflects accessory cell turnover in the irradiated host.(ABSTRACT TRUNCATED AT 400 WORDS)