Analysis of specificity for antigen, Mls, and allogeneic MHC by transfer of T-cell receptor α- and β-chain genes

Abstract

The majority of peripheral T lymphocytes bear cell-surface antigen receptors comprised of a disulphide-linked αβ dimer¹. In an immune response, this receptor endows T cells with specificities for foreign antigenic protein fragments bound to cell surface glycoproteins encoded in the major histocompatibility complex (MHC)^2–5. At a high frequency (>1%), the same population of T lymphocytes responds to allogeneic MHC glycoproteins^6–8, or to differences at other genetic loci termed Mls^8,9, in conjunction with MHC¹⁰. The αβ-antigen receptor has been implicated in alloreactivity^11–13 and Mls reactivity^14–18. In fact, many monoclonal T-cell lines recognize a foreign protein fragment bound to self-MHC molecules and, in addition, recognize allogeneic MHC glycoproteins^19–21, an Mls-encoded determinant ^22–24, or both²⁵. For at least one T-cell clone, a monoclonal antibody directed against the αβ antigen receptor has been shown to block activation induced by either antigen-bound self-MHC or by allogeneic MHC²⁶. However, it remains to be demonstrated directly that a single αβ receptor can mediate antigen specificity, alloreactivity and Mls reactivity, a prerequisite to understanding the structural basis of these high-frequency cross-reactivities. To address this issue we have performed transfers of receptor chain genes from a multiple-reactive T-cell clone into an unrelated host T lymphocyte. We now demonstrate definitively that the genes encoding a single αβ-receptor chain pair can transfer the recognition of self-MHC molecules complexed with fragments of antigen, allogeneic MHC molecules, and an Mls-encoded determinant (presumably in conjunction with MHC). In this case the transfer of antigen specificity and alloreactivity requires a specific αβ-receptor chain combination, whereas Mls reactivity can be transferred with the β-chain gene alone into a recipient expressing a randomly selected α-chain.