Antigenic challenge induces B lymphocytes to proliferate and differentiate provided they receive the appropriate cooperation of T cells, accessory cells and cytokines. This proposal focuses on the B lymphoblast as an important intermediary in the development of B cell responses. The initial goal of this proposal is to identify factors which stimulate efficient growth and/or Ig secretion of B blasts. This will provide a defined biological system in which to proceed with our second aim which is to study the receptors of the B blast that mediate function. We will focus our studies on blasts generated under conditions in which subsequent proliferation and/or Ig secretion is dependent on T cells or T cell derived lymphokines. Our source of B blasts will include cells present in situ (large splenic B cells), and blasts generated in vitro by activation with anti-Ig or by alloreactive T cell blasts. We will determine if there are subpopulations of B lymphocytes that differ in their stimulatory requirements and/or potentials for differentiation. Our main thrust will be to characterize a 44 kilodalton activated T cell product(s) which derives B blasts to proliferate and secrete IgM (BCGF). Our studies will also include responses to already characterized cytokines such as BSF-1 (IL-4), interleukin 1 (IL-1), IL-2, IL-3 and immune interferon. Once we have defined the requirements for B blast formation and function we will identify B blast cell surface receptors that mediate function. We are particularly interested in identifying the receptors for BCGF and bacterial lipopolysaccharides (LPS). Our main approach will involve raising monoclonal antibodies (mAb) to defined populations of B blasts which will be screened in binding and functional assays of B blasts. We have already characterized a mAb 6B7C that detects an epitope of the receptor for IgG (Fc gamma R) that is unique to activated B cells. We propose to characterize the structure and function of B blast Fc gamma R by comparing the structure of the B cells and B blast Fc gamma R which are antigenically distinct and probing the function of B blast Fc gamma R using the two anti-Fc gamma R mAb 2.4G2 and 6B7C.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Immunobiology Study Section (IMB)
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Rockefeller University
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New York
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Pure, E; Cuff, C A (2001) A crucial role for CD44 in inflammation. Trends Mol Med 7:213-21
Li, H L; Davis, W; Pure, E (1999) Suboptimal cross-linking of antigen receptor induces Syk-dependent activation of p70S6 kinase through protein kinase C and phosphoinositol 3-kinase. J Biol Chem 274:9812-20
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Pure, E; Tardelli, L (1992) Tyrosine phosphorylation is required for ligand-induced internalization of the antigen receptor on B lymphocytes. Proc Natl Acad Sci U S A 89:114-7

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