|The intracellular distribution of B cell receptor-internalized antigen (red), and lipid raft-internalized cholera toxin (green) within a murine B lymphocyte. See The Journal of Immunology for details.|
Cell Biology and Molecular Mechanisms of Antigen Processing and Presentation
Antigen presentation to CD4 helper T cells is an important step in the development of an immune response. MHC class II-restricted presentation of antigen by B lymphocytes is important for full development of an antibody-based immune response, while class II-restricted antigen presentation by macrophages is critical for macrophage activation and the control of intra-macrophage pathogens, such as F. tularensis. The long-term goal of the laboratory is to gain a better understanding of the cell biology and molecular mechanisms that underlie exogenous antigen processing and MHC class II-restricted antigen presentation.
B lymphocytes – B cell antigen processing occurs subsequent to antigen binding by the B cell receptor (BCR) and can be divided into 3 general steps: antigen-BCR internalization, intracellular antigen processing, and class II-restricted antigen presentation. Presently, Kathleen McCabe (Ph.D. Graduate Student) is working to better define the molecular mechanisms of BCR internalization. Kathleen will also extend the work of Adriana Caballero Muniz (former Student), and establish the impact of BCR signaling on the mechanism of BCR internalization.
Turning to the next step in the antigen pathway, Bhuvana Katkere (Ph.D. Graduate Student) and Sarah Rosa (Technician) are working is to extend the published studies of Lisa Drake (Technician), Tim Gondré-Lewis (former Postdoc) and Erica McGovern (former Student) to further establish the mechanism of BCR-mediated antigen processing. One particular goal is to better define the role of BCR ubiquitination in controlling delivery of antigen-BCR complexes to MIIC-like antigen processing compartments.
Finally, in collaboration with Jon Harton (CIMD), Elizabeth Sargent (Technician) is working to extend the studies of Toufic Nashar (former Postdoc) and establish the role of MHC class II subsets in both MHC class II-mediated B cell signaling and presentation of cognate antigen-derived peptides to CD4 T cells.
– Macrophages can process and present antigen to CD4 T cells, and this event is critical for macrophages activation and growth control of intra-macrophage pathogens such Francisella tularensis. Justin Wilson (former Ph.D. Graduate Student) has established that F. tularensis elicits macrophage prostaglandin E2 production, which results in altered CD4 T cell cytokine responses as well as the down-regulation of class II by neighboring activated macrophages. Presently, Danielle Hunt (Technician) is working on extending these studies by establishing the mechanism of F. tularensis processing and presentation.
The overall goal of these studies is to better establish the cell biology and molecular mechanism underlying MHC class II-restricted antigen processing and presentation. This information will aid in the design of more effective vaccines and immunotherapies.