Search

Autoimmune diseases are often mediated by self-reactive T cells, which must be activated to cause immunopathology. One mechanism, known as molecular mimicry, proposes that self-reactive T cells may be activated by pathogens expressing crossreactive ligands. Here we have developed a model to investigate how the affinity of the T-cell receptor (TCR) for the activating agent influences autoimmunity. Our model shows that an approximately fivefold difference in the TCR affinity for the activating ligand results in a 50% reduction in the incidence of autoimmunity. A reduction in TCR-ligand affinity to approximately 20 times lower than normal does not induce autoimmunity despite the unexpected induction of cytotoxic T lymphocytes (CTLs) and insulitis. Furthermore, in the absence of a key negative regulatory molecule, Cbl-b, 100% of mice develop autoimmunity upon infection with viruses encoding the lower-affinity ligand. Therefore, autoimmune disease is sensitive both to the affinity of the activating ligand and to normal mechanisms that negatively regulate the immune response. [ABSTRACT FROM AUTHOR]

Defects in natural killer T (NK T) cell function and of interleukin-4 -production in SJL and NOD mice have been linked to susceptibility to autoimmune disease. As SJL and NOD mice both carry the T-cell receptor (TCR) α-chain locus "c" (Tcrac) haplotype, found in few other strains, we have attempted to determine the influence of Tcra polymorphism on NK T-cell recognition of ligand, selection, and immune responses. The majority of NK T cells use an "invariant" TRAV11J15 (previously called AV14J18 or Vα14 Jα281) α- chain paired with either TRBV13–2, BV29, or BV1 to recognize ligands presented by mCD1 molecules, including the glycolipid α-galactosylceramide (α-GalCer). Sequencing of TRAV11 from the mouse strains B10.A (encoding the Tcrab haplotype), B10.A-Tcrac, and NOD (Tcrac) shows that Tcrac has a single TRAV11 gene (TRAV11*01) and that Tcrab has a single expressed gene (TRAV11*02), plus a closely related pseudogene. There is no apparent difference in α-chain J-region usage or in the CDR3α sequence at the TRAV11-J15 junction between the haplotypes in TRAV11-bearing NK T cells. Using Biacore and tetramer-binding and decay assays, we have determined that the interaction between Tcrac TRAV11*01 NK T TCR and the mCD1/α-GalCer complex is slightly weaker than that of Tcrab (i.e., TRAV11*02) NK T TCR. These differences are minor compared with differences between agonist and antagonist ligands in other TCR systems, suggesting that it is unlikely that TCR polymorphism explains the defect in NK T cells in the autoimmune mouse strains. [ABSTRACT FROM AUTHOR]