Malini Raghavan, Ph.D.
The major histocompatibility complex (MHC) genetic locus exerts powerful influences on outcomes in infectious and inflammatory diseases and cancers. MHC class I molecules, comprising a plasma membrane-linked heavy chain, an invariant light chain (beta2-microglobulin) and a short peptide, control immune responses mediated by CD8+ T cells and natural killer (NK) cells. In humans, MHC class I heavy chains are encoded by the human leukocyte antigen (HLA) HLA-A, HLA-B and HLA-C genes. Each locus is highly polymorphic, and the polymorphisms influence the peptide-binding characteristics of HLA class I proteins. Diverse T cell receptors (TCR) of CD8+ T cells are specific for particular HLA class I-peptide complexes, which initiate CD8+ T cell activation, following TCR ligation. Antigen receptors on NK cells also recognize specific HLA-C, HLA-B or HLA-A allotypes, to induce NK cell activation or inhibition.
Our recent studies demonstrate that HLA-B polymorphisms influence the conformational and intracellular assembly characteristics of HLA-B allotypes, their cell surface expression levels, and the expression of peptide-deficient (empty) forms. Our current studies are focused on understanding unconventional HLA-B assembly and trafficking pathways and their consequence for anti-viral immunity, as well as the functions of empty HLA-B allotypes in the immune response.
The endoplasmic reticulum (ER) is the cellular hub for the folding of MHC class I molecules and many other cell surface and secreted proteins. Protein chaperones such as calreticulin play important roles in mediating protein folding in the ER and in maintaining quality control of folding integrity. Our current studies are focused on understanding roles for calreticulin in the maintenance of ER homeostasis under conditions where misfolded proteins accumulate. Mutations of the C-terminal acidic calcium-binding domain of calreticulin are linked to myeloproliferative neoplasms. We study the mechanisms by which calreticulin mutations lead to dysregulated cellular signaling and neoplastic transformation.