Research SummaryControl of T Cell Biochemistry by MHC alleles
It is thought that host pathogen interactions have driven the evolution of the immune system. In mammals, the major histocompatibility complex (MHC) is the most rapidly evolving locus under such evolutionary pressure. Not surprisingly, genome wide association studies have implicated the MHC locus in many diseases, including autoimmune diseases. Allelic variations at the MHC locus have been correlated with the type of immune response observed. We currently lack a detailed molecular understanding of this phenomenon. My research work will focus on understanding how allelic variation in MHC may impose different developmental program in T cells and if this could in part explain the correlation between MHC alleles and the type of immune response.
The MHC locus encodes many genes, among them are MHC class I and class II molecules that present self and pathogen derived peptides. T cells express on their surface, T cell receptors (TCRs) that interact with peptide bound MHC molecules. During T cell development in the thymus T cell clones bearing TCRs that interact with self-peptide loaded MHC with high affinity undergo negative selection and are eliminated. Only T cell clones that interact self-peptides with weak to moderate affinity undergo positive selection and maturation. This developmental process to a large extent keeps autoimmunity in check. In addition to the TCR, T cells also express coreceptors CD4 and CD8 that play an important role in T cell development by interacting with MHC class II and MHC class I respectively. The cytoplasmic tails of the co-receptors interact with the kinase Lck, which phosphorylates the TCR. The coreceptors are thought to function by bringing Lck in proximity to the TCR engaging peptide-bound MHC. The spatial and temporal dynamics of these molecules when T cells are undergoing positive and negative selection are largely unknown.
My approach will be to develop cutting edge microscopy techniques to study the distribution of molecules in live cell-cell interfaces and break barriers of spatial and temporal resolution experienced in 3D confocal microscopy. I will combine imaging experiments with biochemical and functional assays in an interdisciplinary approach to study the rich and diverse biology of MHC molecules
Figure Legend: Overview of the MHC region with validated GWAS associations from the NHGRI GWAS catalog (https://www.genome.gov/gwastudies/) plotted as a function of position along chromosome 6 (hg18). Strongest SNP associations are annotated by trait or disease. Classical HLA-A, -B, -C, -DP, -DQ and -DR genes are highlighted (red vertical ticks) among the many hundreds of genes across the region. (Figure and legend reproduced from: de Bakker PI, Raychaudhuri S. Interrogating the major histocompatibility complex with high-throughput genomics. Hum Mol Genet. 2012 Oct 15;21(R1):R29-36.).