Molecular Basis of Immune Recognition
The study of histocompatibility in man and in other vertebrates has led to the understanding of the mechanisms of immune recognition and to the discovery of novel molecules and cells involved in these processes, including class I and class II proteins encoded in the major histocompatibility complex (MHC) of all vertebrates examined and T cell receptors. The normal human response to bacterial and viral infection involves these molecules and results in either the generation of T helper cells and antibodies or of cytotoxic T-lymphocytes. In addition, many important human autoimmune diseases are linked to particular alleles of the class I and class II proteins.
In particular, the recognition by CD4+ T cells of peptides bound to class II MHC (MHCII) and exposed on the surface of antigen presenting cells initiates an adaptive immune response. Antigen presentation is a multistep process involving the intracellular fragmentation of protein antigens, followed by binding of the derived peptide epitopes to MHCII with the participation of the peptide-editing molecule DM, and subsequent transport to the surface for recognition. Our long-term goal is to sufficiently characterize the stages of this process so that we can predict T cell responses.
● The biochemical and biophysical bases of binding of antigenic peptides to MHC II molecules and the correlation between binding thermodynamics, structure and biology of the peptide/MHCII complex.
● The mechanism by which DM skews the repertoire of peptide/MHCII complexes presented to CD4+ T cells in favor of the most stable complexes.
● Developing an in silico binding prediction algorithm based on the in vitro observations, with specific clinical application, such as development of inhibitors in Hemophilia A patients.