MHC molecules associated with autoimmunity possess known structural features that limit the repertoire of peptides that they can present. Such limitation gives a selective advantage to TCRs that rely on interaction with the MHC itself, rather than with the peptide residues. At the same time, negative selection is impaired because of the lack of negatively selecting peptide ligands. The combination of these factors may predispose to autoimmunity. We found that mice with an MHC class II–peptide repertoire reduced to a single complex demonstrated various autoimmune reactions. Transgenic mice bearing a TCR (MM14.4) cloned from such a mouse developed severe autoimmune dermatitis. Although MM14.4 originated from a CD4⁺ T cell, dermatitis was mediated by CD8⁺ T cells. It was established that MM14.4⁺ is a highly promiscuous TCR with dual MHC class I/MHC class II restriction. Furthermore, mice with a limited MHC–peptide repertoire selected elevated numbers of TCRs with dual MHC class I/MHC class II restriction, a likely source of autoreactivity. Our findings may help to explain the link between MHC class I responses that are involved in major autoimmune diseases and the well-established genetic linkage of these diseases with MHC class II.

Peripheral T lymphocytes can be subdivided into naive and antigen-experienced T cells. The latter, in turn, are represented by effector and central memory cells that are identified by different...

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Complications after vaccination, lack of vaccines against certain infections, and the emergence of antibiotic-resistant microorganisms point to the need for alternative ways of protection and treatment of infectious diseases. Here, we proposed a therapeutic approach to control salmonellosis based on adoptive cell therapy. We showed that the T cell receptor (TCR) repertoire of salmonella-specific memory cells contains 20% of TCR variants with the dominant-active α-chain. Transduction of intact T lymphocytes with the dominant salmonella-specific TCRα led to their enhanced in vitro proliferation in response to salmonella. Adoptive transfer of transduced T cells resulted in a significant decrease in bacterial loads in mice infected with salmonella before or after the adoptive transfer. We demonstrated that adoptive immunotherapy based on T cells, transduced with dominant-specific TCRα could be successfully applied for treatment and prevention of infectious diseases and represent a useful addition to vaccination and existing therapeutic strategies.

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.