FUNCTION OF CD19 IN B CELL DEVELOPMENT &DIFFERENTIATION

University Of California San Diego, La Jolla CA

Investigators

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Abstract

DESCRIPTION (Adapted from the Investigator's Abstract): Antigen receptor-mediated signaling is the key determinant governing B lymphocyte activation, differentiation or death. Molecules that modulate signals through the B cell receptor (BCR) can thus be instrumental in determining B cell fate. Much attention has been given to intracellular intermediates acting downstream of the BCR. This proposal addresses the biological role of the B cell "co-receptor" CD19 which, in the appropriate context, can augment BCR-mediated B cell activation and proliferation. The investigator has found that CD19--deficient mice are impaired in B cell lymphopoiesis and in responding to T cell-dependent antigens, and he proposes to determine the molecular basis for these defects in the context of CD19 association with the BCR and the CD19/CD21 (complement receptor 2)/CD81 complexes. In Aim 1 the role of CD19 in early B cell development will be examined, focusing on developmental checkpoints regulated by pre-BCR or BCR signaling. This involves a comparative analysis of CD19-/- and wildtype mice, which will be refined by the use of pre-BCR mutant mice and immunoglobulin transgenic mice bred onto the CD19 null background. As CD19-/- mice exhibit a severe reduction in B-1 (formerly ly-1) B cells, in Aim 1b they will determine whether this deficiency is mainly attributed to inefficient generation, expansion or maintenance of this important subpopulation of B cells. Aim 2 addresses the role of CD19 in the recognition of and activation by foreign antigen. It will be determined whether CD19 acts as the signaling moiety of the CD19/CD21/CD81 complex, which is known to synergize with surface immunoglobulin in the co-recognition of opsonized (C3d-bearing) foreign antigen. Immunizations will be accompanied by flow cytometric and immunohistochemical techniques to assess B cell differentiation, migration and survival. Aim 3 will delineate the dual roles of CD19 as both a member of the CD19/CD21/CD81 complex and also as an elementary component of the BCR. This will be accomplished by complementation of the CD19 null mutation with transgenes encoding modified CD19 molecules which associate exclusively with the BCR or CD19/CD21/CD81 complexes. This genetic approach will assess the relative contribution of CD19 to the function of these crucial signaling complexes in effecting B cell differentiation and antibody production.