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Malini Raghavan

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Primary Appointment: Microbiology and Immunology
Primary PIBS Dept.: Microbiology and Immunology
Other PIBS Depts.: Biophysics
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 DESCRIPTION OF RESEARCH
  The interaction between a T cell receptor (TCR) on a CTL and an MHC class I-peptide complex on an antigen presenting cell (APC) initiates many anti-viral and anti-tumor immune responses. MHC class I molecules comprise a membrane-linked heavy chain, a soluble light chain (β2-microglobulin; β2m) and a short peptide bound in a groove of the membrane-distal domains of the heavy chain. Complexes of MHC class I heavy chains, β2m and peptide are typically assembled in the ER of cells via a complex assembly pathway. In the classical MHC class I assembly pathway, cytosol-derived antigens that are endogenous to cells are processed into peptides by the proteasome. The proteasome generates peptides optimized for MHC class I binding at the C-terminus, but extended at the N-terminus relative to peptides bound to mature MHC class I molecules. N-extended peptides are transported into the ER lumen by the TAP transporter. In the ER, MHC class I heterodimers lacking peptides are recruited into complexes with the TAP transporter, in an interaction bridged by tapasin. ERp57, PDI, and calreticulin also associate with the TAP-tapasin-MHC class I complex to form a large complex called the peptide loading complex (PLC). Components of the PLC facilitate peptide binding to MHC class I molecules. ERAAP cleaves N-extended peptides at the N-terminus, optimizing MHC class I-peptide associations. Peptide occupancy triggers dissociation of MHC class I from the PLC, exit from the ER, and transit to the cell surface, where the MHC class I molecules become available for immune surveillance by T cells. This general pathway is relevant to the assembly of MHC class I-peptide complexes in virally infected cells and tumor cells, and to the subsequent immune recognition of such cells. Our laboratory studies all of the molecular components of the MHC class I assembly pathway, in order to better understand how MHC class I assembly is orchestrated in a cell.

Human MHC class I molecules are highly polymorphic, and recent studies have shown that different MHC class I allotypes differ dramatically in their intracellular assembly requirements. For example, HLA-B*4402 is highly tapasin dependent for its assembly, whereas HLA-B*4405 is relatively tapasin independent. Mechanisms that govern these assembly differences and the functional effects of such differences are of considerable interest to us, as the assembly profile could impact the efficiency of the immune response to tumors and intracellular infections.

The initial priming of naïve CD8+ T cells into effector CTL, requires the processing of exogenous particulate and soluble antigens by dendritic cells (DC), and presentation of such antigens via the MHC class I molecules of the DC. This phenomenon is called cross-priming and is a key mechanistic step in the initial activation of CTL responses against tumor cells, viruses and other intracellular pathogens. Our research is also focused on understanding cellular pathways used by antigen presenting cells (APC) for the presentation of exogenous antigens to CD8+ T cells. We are additionally interested in defining antigen uptake systems that can enhance the cross-priming efficiency, which will be important towards vaccine develpment.