Immature B Cell Antigen Presentation Defects

University Of Pennsylvania, Philadelphia PA

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Abstract

DESCRIPTION: (Adapted from Applicant's Abstract) A comprehensive didactic program in immunology provided by the Immunology Graduate Group in the early part of the award period will be followed by an increasingly immersive and structured experience in laboratory research. Seminars, journal clubs, and various forums for presentations will complement the research training. The goal is to provide the Candidate with the foundation and the means to develop into an independent investigator. Signaling through the B cell receptor (BCR) in immature B cells leads to cell cycle arrest and apoptosis. This ability to undergo negative selection plays a major role in maintaining tolerance to self antigens. Negative selection can be modulated by cognate T cell help but little is known about the nature of the interaction between immature B cells and naive T cells. This interaction is essential in the development of the B cell repertoire and must be understood in detail if we are to explain tolerance and autoimmunity. Preliminary data suggest that mature and immature B cells differ in the way they process and present antigen to T cells. Upon BCR ligation, immature B cells fail to up regulate the co-stimulatory molecule B7-2 and also do not exhibit reorganization and fusion of the late endosomal vesicles where peptide loading onto MHC class II molecules takes place. Functionally, immature B cells do not appear to present antigens to cognate naive T cells as effectively as mature B cells. Lastly, we found that immature B cells do not mobilize lipid rafts to the same degree as mature B cells, a characteristic that may contribute to these differences in antigen processing and presentation through defects in BCR mediated signal initiation. The proposed studies are directed at establishing the mechanisms for the developmental differences in immature B cell antigen processing and presentation compared with mature B cells. We also seek to determine how developmental differences in BCR mediated signal transduction contribute to the differences in antigen processing and presentation in immature B cells.