Important progress has been made in understanding the process by which T lymphocytes recognize antigen through the cloning and characterization of the alpha and beta genes of the T cell receptor for antigen (TCR). Despite this progress, the mechanism by which T lymphocytes recognize antigen in association with a product of the major histocompatibility locus (MHC), termed dual recognition, remains to be elucidated. This process has particular importance to our understanding allograft rejection and tolerance, which is critical for improving the success of renal and bone marrow transplants. It is becoming increasingly likely that understanding the expression of the alpha and beta genes alone will not explain dual recognition, and recent data from several laboratories suggest that additional TCR genes are involved. One such putative gene, termed gamma, has been isolated but remains poorly characterized. This project aims to define additional human T cell receptor genes with the goal of better understanding the process of dual recognition. We have begun searching for additional human TCR genes which are postulated, like gamma, to participate in dual recognition. The initial approach has been to cross-hybridize a highly conserved region of mouse TCR genes selected by computer analysis with human genomic clones. This strategy, when applied previously by other laboratories for screening MHC genes, was useful in identifying new, unsuspected MHC genes. We have obtained a genomic clone, SLE1, which cross hybridizes with our murine TCR probe but is not the known human alpha, beta, or gamma genes. We are in the process of characterizing this clone to determine if it is a true TCR gene, but similar to authentic TCR genes, we have seen rearrangement of this gene in the DNA derived from some human T cell tumors. Subsequent studies will also employ antigen-specific human suppressor cells, which do not transcribe the beta TCR gene, and so must be using additional genes for antigen recognition.
