A unique population of B-lymphocytes, termed B-1, is elevated in certain autoimmune states in mice and humans. Unlike the conventional B-cells (B-2 subset), some B-1 cells express a T-cell differentiation marker CD5 and are primarily found in peritoneal and plural cavities. The B-1 cells can self-renew and have a propensity to make poly-reactive antibodies. B-1 cells fail to proliferate in vitro and undergo apoptosis in vivo in response to B-cell receptor (BCR) cross-linking whereas B-2 cells undergo clonal expansion. Similarly, B-2 but not B-1 cells proliferate to stimulation with antibodies to CD72, a B-cell differentiation antigen. Based on our recent studies with CD5-/- mice, the investigator postulates that CD5 acts as a negative regulator of B-1 cells by interfering with BCR induced signal transduction in B-1 cells.
Our specific aims are: 1) The investigator will test the possibility that CD5 inhibits BCR signaling in B-1 cells by recruiting an SH2 domain containing protein tyrosine phosphatase (SHP-1). He will identify the regions of CD5 cytoplasmic domains involved in binding to SHP-1 and test the in vivo relevance of such interaction for B-1 cell responses. 2) The investigator will define the BCR induced biochemical signaling events that are regulated by CD5-SHP-1 interaction in B-1 cells. He will examine the role of Src and non-Src family protein tyrosine kinases, CD19, MAP kinases as well as activation of the transcription factors NF-AT and NF-kappa-B. 3) He will test the hypothesis that receptors other than CD5 will also participate in negative regulation of B-1 cells, especially the B-1 subset that does not express CD5. 4) Since CD72 responses are not restored in CD5-/- mice, the investigator will test the hypothesis that B-1 cells signaling is regulated by a novel mechanism that is independent of CD5. 5) The investigator proposes that CD5 is important for keeping self-reactive B-1 cell in check. This will be tested by examining the effect of CD5 expression on the recruitment of self and foreign antigen specific B-cells in to B-1 compartment of BCR transgenic mice bred to CD5-/-mice. He will determine if absence of CD5 affects B-cell tolerance and enhances autoantibody production in such CD5-/- -transgenic hybrids. These studies should lead to the development of better means of controlling autoimmune diseases and B-cell leukemia.
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