This research proposal is designed to determine if the unique activation requirements of the Ly1+ subset of B lymphocytes provide an explanation and insight into the regulatory role of these cells, particularly as it relates to the development of autoimmune phenomenon. Although the Ly1+ B cells form a minor subset (less than 2% of the normal splenic population), they appear to have profound regulatory functions. They can augment idiotype-specific responses to hapten-carrier complexes, induce suppressor cells, produce B-specific growth factor(s) and are the source of a large portion of the autoreactive IgM antiboides. Preliminary data indicate that these cells also have unique activation requirements, responding differentially to the T cell lymphokines interleukin 2 and B cell growth factor II. It is not clear that these cells absolutely require activation through antigen-specific surface immunoglobulin receptors to enter the cell cycle. They may also be limited in their ability to switch to IgG production. These unique properties suggest that the Ly1+ B cell may be activated and release regulatory lymphokines under conditions which do not significantly activate the predominant Ly1- B cell population. The release of these regulatory lymphokines may then modulate the antigen/lymphokine reactivity of the Ly1- population. To evaluate these possibilities, subset-specific lymphokines will be identified, and the effects of these lymphokines will be delineated in terms of receptor expression, cell-cycle progression, second messenger systems and gene regulation of both oncogenes and the immunoglobulin locus. The possible role of the Ly1 antigen as a lymphokine receptor will be specifically addressed. The function of the autocrine B cell growth factor produced by the Ly1+ cells in the regulation of proliferation of the Ly1- population will be examined. The nature of this regulation will be examined relative to a) whether this soluble mediator is sufficient for modulation of Ly1-B cell activation or b) if direct membrane-to-membrane contact is also required. Both Ly1+ and Ly1-neoplastic B cell clones and FACS- enriched normal Ly1+ B cells will be used for these studies.
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