The two main antigen receptors in the jawed vertebrate immune systems that recognize antigens specifically are the B and T cell receptors. Although both receptors are generated by the same genetic mechanisms and possess an overall similar structure, they recognize antigenic ligands in fundamentally distinct ways. BCRs recognize conformational epitopes, whereas TCRs recognize small antigenic structures, often peptides derived from antigenic proteins, bound to molecules of the Major Histocompatibility Complex (MHC). The molecular basis for this MHC restriction remains essentially unknown. The proposed studies aim at testing the hypothesis that the TCR repertoire is predisposed to recognize MHC molecules in the absence of any selective pressure. Furthermore, we propose to identify the rules, if they exist, that drive this interaction. With the recent advance of the se of chimeric T cell antigen receptors as a promising form of cancer immunotherapy, an understanding of this phenomenon is absolutely fundamental. By gaining an appreciation for why and how TCRs recognize MHC, we can harness its power to better understand and modulate immune responses to infections, tumors, or transplants.
The two main antigen receptors that can specifically recognize antigens in the jawed vertebrate immune systems are the B and T cell receptors. Although both receptors are generated by the same genetic mechanisms and possess an overall similar structure, they recognize antigenic ligands in fundamentally distinct ways. Antigen receptors on B cells recognize conformational epitopes that can be found on native proteins, whereas TCRs recognize small antigenic structures, often peptides derived from antigenic proteins, bound to molecules of the Major Histocompatibility Complex (MHC). The molecular basis for this MHC restriction remains unknown albeit intense research on the subject over the past 50 years. The proposed studies aim at testing the hypothesis that randomly generated TCR molecules are predisposed at recognizing MHC molecules. An understanding of this phenomenon is of fundamental importance for our comprehension of how the TCR recognize peptide-MHC complexes, one of the central mechanisms of immune activation, so that it can be exploited for therapeutic usage to improve human health.
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