Jim Drake, PhD

MHC Class II-Restricted Antigen Presentation to CD4 Helper T Cells

Major histocompatibility (MHC) class II-restricted antigen presentation to CD4 helper T cells is a key step in the development of an immune response.  Class II-restricted antigen presentation to CD4 T cells by B lymphocytes is important for full development of an antibody-based immune response.  The long-term goal of the laboratory is to gain a better understanding of the cell biology and molecular mechanisms that underlie antigen processing and MHC class II-restricted antigen presentation.

Class II molecules are an alpha-beta heterodimer and work done in collaboration with Dr. Ann Dixon (Warwick University) has revealed that alternative pairing of transmembrane (TM) domain GxxxG dimerization motifs results in the formation of two different class II conformers (i.e., M1- and M2-paired class II).  These MHC class II conformers were originally identified and characterized in mouse I-A^k class II, but recent work has extended this model of human HLA-DR class II.

In B cells, M1- and M2-paired class II are loaded with processed antigen (peptides) from distinct sources and the class II conformers have distinct signaling properties.  M1-paired class II is efficient loaded with peptide derived from B cell receptor (BCR)-bound cognate antigen engagement of these complexes drives B cell activation.  In contrast, M2-paired class II is loaded with peptides derived from non-cognate antigen internalized by fluid-phase endocytosis and engagement of these complexes fails to activate the cells (and can lead to cell death).

Ongoing studies are focused on:

• Elucidating the molecular mechanisms by which peptides from BCR-bound antigen are selectively loaded onto M1-paired class II
• Defining the structural differences between M1- and M2-paired class II
• Defining the peptidomes of M1- and M2-paired class II under various conditions