Advanced Course in Immunology On Demand Lecture Recordings-MHC-restricted Antigen Presentation to T Cells

Video Transcription

Video Summary

The lecture explained how antigen presentation works at the molecular level and why it is central to immunity, autoimmunity, and cancer. It began with the landmark HLA-A2 crystal structure, which revealed how MHC class I molecules bind peptide antigens in a groove. The MHC locus on chromosome 6 is highly diverse, with thousands of alleles, and this diversity helps populations resist pathogen escape.<br /><br />The speaker then reviewed antigen-presenting cells, especially dendritic cells, which capture antigens in tissues, travel to lymph nodes, and activate T cells or induce tolerance. Dendritic cell maturation depends on pH changes in endosomal compartments, which activate proteases and drive MHC class II trafficking to the cell surface.<br /><br />For MHC class I, peptides are generated in the cytosol by the proteasome, transported by TAP into the ER, and loaded onto class I molecules with help from tapasin, calreticulin, and ERAP. Cross-presentation by specialized CDC1 dendritic cells allows extracellular antigens from dead cells to enter the class I pathway, which is crucial for antiviral and anti-tumor CD8 T cell responses.<br /><br />MHC class II presents longer peptides from endosomal compartments, with invariant chain and HLA-DM controlling peptide loading and exchange. The speaker also described structural studies showing how HLA-DM edits peptide loading by destabilizing weakly bound peptides.<br /><br />Finally, the talk covered disease relevance: HLA polymorphisms influence autoimmune disease risk, especially type 1 diabetes, where specific class II alleles shape peptide presentation of insulin-related antigens and hybrid fusion peptides. In cancer, neoantigen vaccines depend on identifying mutant peptides presented by patient-specific HLA molecules. The lecture ended by emphasizing that effective vaccine and tumor immunity require functional dendritic cell antigen presentation.

Asset Subtitle

Lecture 9: Kai W. Wucherpfennig, Dana-Farber Cancer Institute, Harvard Medical School

Asset Caption

Kai W. Wucherpfennig, Dana-Farber Cancer Institute
MHC-restricted Antigen Presentation to T Cells

Keywords

antigen presentation

MHC class I

MHC class II

HLA polymorphism

dendritic cells

cross-presentation

T cell activation

proteasome

TAP transporter

HLA-DM

autoimmunity

neoantigen vaccines