The central hypothesis of the proposed research is that the IgG Fc receptors (Fc R) on T- and B-lineage progenitor cells influence murine lymphoid cell development by interactions of the FcgR with alternative, non-Ig ligands on hematopoietic stromal cells. Recent findings suggest that FcgRlll (CD16), an ITAM-containing protein kinase-activation receptor, and FcgRll (CD32), an ITIM-containing protein kinase-inhibitory receptor, mediate positive and negative lymphopoietic signals, respectively. The roles of CD16 and CD32 in normal lymphopolesis will be investigated in vivo and in vitro in normal wild-type mice and in genetically-altered mice that carry disrupted FcgR genes. The rationale for these studies is based on: a) pro-T cell and pro-B cell differentiation in vitro are accelerated by experimental manipulation of their FcgRs; b) the absence of the inhibitory FcgR in CD32 gene-targeted mice is associated with higher numbers of bone marrow progenitor B cells and enhanced lgG and IgE antibody responses; c) hematopoietic stromal cells appear to express alternative, non-Ig ligands for FcgRs; and d) during lymphoid cell development CD16, an activation Fe receptor, is present on T- and B-lineage progenitor cells prior to, but not after the cells express clonal antigen receptors (TCR, BCR). A major goal of the proposed research is to isolate and determine the molecular structure and tissue distribution of the alternative, non-Ig ligand (FcgR counter-receptor that is present on some hematopoietic stromal cells. In an extension of the central concept of this research, studies are proposed that will test the hypothesis that in murine lgG myeloma this novel lymphopoietic regulatory mechanism is uncoupled and results in pathologic lymphopoiesis. The rationale for these studies includes the findings that mice with IgG myeloma: a) have prominent abnormalities of T- and B-lymphopoiesis, b) develop large numbers of circulating, adult-thymectomy-sensitive, CD8+ cells that express FcgR; c) exhibit a profound and selective impairment of primary antibody responses; and d) have high circulating levels of soluble FcgR. Preliminary findings of CD16 and CD32 expression on human progenitor B-lineage cells suggest that the information generated in the proposed investigations in this murine model will be relevant to normal and pathologic lymphopoieis in humans.
