MHC restriction and allogeneic immune responses

Discovery of major histocompatability complex (MHC) restriction helped in the understanding of how T-lymphocytes recognize antigens on bacteria, viruses, and tumor cells. It was initially accepted that MHC restriction was a consequence of "adaptive differentiation" in the thymus; during differentiation, the forming repertoire of T-lymphocytes "learned" a low affinity for self MHC molecules via positive selection. This view was later countered by discovery of artifacts in underlying studies and the fact that adaptive differentiation could not explain direct allogeneic and allorestricted recognition phenomena. Data from experiments with TCR transgenic animals, individual MHC/peptide complex expression, and recipients of xenogenic thymus glands yielded evidence of an ability to adapt to microenvironment and a low specificity of positive selection. These facts led to an alternative interpretation of MHC restriction explained, in part, by specificity of a pool of effector cells activated by primary immunization. Details of this phenomenon were defined in studies that noted differential primary structures of peptides that bound various allelic forms of MHC molecules. Here, the T-lymphocyte repertoire formed in the thymus was a result, in part, of random rearrangement of germinal sequences of TCR gene fragments. Such pre-selected repertoires were inherently capable of reacting with different allelic forms of MHC molecules. In contrast, MHC molecules were characterized by significant intraspecies polymorphisms; negative and positive selections were aimed at adaptation of a pre-selected repertoire to a specific microenvironment in an individual. Via elimination of autoreactive clones and sparing of a broad spectrum of specificity to potential pathogens, selection in the thymus could be considered a life-long allogeneic reaction of a pre-selected repertoire to self MHC molecules resulting in tolerance to "self," increased responsiveness to foreign MHC molecules, and cross-reactivity of the mature T-lymphocyte repertoire to individual foreign peptides plus self MHC.