T-cell Antigen Receptor Repertoire Research Articles

Profound alteration in an alpha beta T-cell antigen receptor repertoire due to polymorphism in the first complementarity-determining region of the beta chain.

Amino acid residues that are critical in maintaining the framework structure of immunoglobulin heavy- and light-chain variable (V) regions are strongly conserved in the V alpha and V beta proteins of the alpha beta T-cell antigen receptor (TCR alpha beta). Consequently, it has been proposed that TCR alpha beta has a conformation similar to that of an immunoglobulin Fab fragment and that the regions of the TCR homologous to the three immunoglobulin complementarity-determining regions (CDRs 1, 2, and 3) bind to the peptide antigen-major histocompatibility complex (MHC) molecule ligand. A single amino acid substitution in the predicted CDR1 of the V beta 3 protein of certain mouse strains dramatically altered TCR alpha beta usage in an antigen-specific MHC-restricted immune response but did not abrogate V beta 3 specificity for the superantigens minor lymphocyte stimulatory locus (Mls)c and staphylococcal enterotoxin A (SEA). The results confirm the importance of the V beta CDR1 in antigen-MHC molecule recognition, supporting the Fab-like structural model of TCR alpha beta, and provide further evidence that conventional antigen-MHC recognition and superantigen recognition are mediated by distinct regions of the TCR beta chain. They also suggest that allelic polymorphism may be a significant source of diversity in the TCR repertoire.

Antigen receptors and adhesion molecules on T lymphocytes in the gut

The gut-associated lymphoid tissue represents an important site of initial contact with foreign antigens from the intestinal lumen. It is a complex immune system comprising of Peyer's patches, mesenteric lymph nodes, mucosal lymphocytes present in the lamina propria, and intraepithelial lymphocytes located on the luminal surface of the basement membrane and adjacent to the basolateral side of enterocytes. The function and immunoregulation of the gut-associated lyphoid tissue and its role in the pathogenesis of intestinal diseases are only partly understood. We summarize selected advances in understanding the cell-surface molecules involved in homing and adhesion of T cells in the gut-associated lymphoid tissue and the nature of the T-cell antigen receptor repertoire expressed by intraepithelial lymphocytes.

Positive selection of CD4+ thymocytes controlled by MHC class II gene products.

The mature T-cell antigen receptor repertoire is characterized by lack of reactivity to self-components as well as by preferential reactivity to foreign antigens in the context of polymorphic self-proteins encoded within the major histocompatibility complex. Whereas the former characteristic (referred to as negative selection or tolerance) is associated with intrathymic deletion of T cells expressing T-cell antigen receptor beta-chain variable (V beta) domains, which confer a preferential reactivity to self antigens, the existence of the latter (referred to as positive selection or MHC restriction) has so far only been inferred indirectly from functional studies. We show here that intrathymic deletion of V+beta 6 T cells (reactive with a self-antigen encoded by the Mlsa locus) is controlled by polymorphic MHC class II determinants. Furthermore, in mice lacking expression of Mlsa, the same class II MHC loci control the frequency of occurrence of V+beta 6 cells among mature CD4+ T lymphocytes. These data are direct evidence for positive selection by MHC determinants in the thymus in unmanipulated animals.

Functional alpha and beta T cell chain receptor messages can be detected in old but not in young athymic mice.

The expression and sequences of T cell antigen receptor (TcR) alpha and beta-chain genes were investigated in the spleens from congenitally athymic (nude) mice. A small number of Thy-1+ cells (approximately 7.0%) was found in nylon wool-enriched spleen cells from young (8 weeks old) nude mice but no L3T4 or Lyt-2 surface antigens were detected. These nude mice expressed only a low level of 1.0-kb beta-chain mRNA and little or no alpha-gene transcripts. On the other hand the number of Thy-1+ spleen cells increased slightly (to 24%) in old (20 weeks old) nude mice and a small number of L3T4+ (10%) and/or Lyt-2+ (5%) cells were detectable. "Full length" 1.7-kb alpha-chain and 1.3-kb beta-chain messages could be found in nylon wool-enriched spleen cells from old nude mice. Sequence analysis of the cDNA revealed that no functional alpha and beta-chain genes can be detected in the spleen cells of young athymic mice while some of the old mice with nu/nu genotype are composed of completely rearranged V-(D)-J-C-gene segments which encode potentially functional proteins. Interestingly, two of three independent cDNA clones encoding the alpha chain used the same V alpha and J alpha-gene segments. These results suggest that extrathymic TcR alpha and beta-chain gene rearrangements do occur, though slowly, to some extent, in nude mice and may be responsible for the limited antigen and/or H-2-related T cell functions in these old athymic mice. The data further suggests that the TcR repertoire in athymic mice may also be limited.