Natural killer (NK) cells can recognize and lyse not only sensitive tumor cells but also certain normal cell types such as bone marrow cells and thymocytes. Recently, NK cells have been shown to also affect B cells. The purpose of this work is to explore the ways in which NK cells may interact with and regulate B cells and hence the antibody response. Three lines of investigation will be followed: (1) The possible role of NK cells in regulating the magnitude and kinetics of primary and secondary Ab responses to T-independent and T-dependent antigens will be analyzed in vivo and in vitro. The antigens to be used include TNP-Brucella abortus (a TI-1 antigen)-- TNPFicoll (TI-2), and TNP-sheep RBC (TD). Using our model for in vivo depletion of NK cells with NK1.1 alloantiserum, we will test whether depletion of NK cells allows a heightened Ab response (as indicated in preliminary experiments with SRBC) to both T-independent and T-dependent antigens. Whether this effect involves intersctions with T cells will be further analyzed in vitro by depletion of NK cells with anti-NK1.1 and C or addition of either NK cells enriched from normal spleen or cloned NK cell lines. (2) The mechanisms by which NK cells may affect B-cell responses will be probed in experiments to test whether B cells express NK-target antigens during the course of their differentiation/maturation. Mitogen- and antigen-stimulated B cells as well as B-cell lines will be analyzed for expression of cell surface markers, stage of cell cycle, and susceptibility to binding and lysis by NK cells using a multiparameter analysis and flow cytometry. (3) Finally, to begin to dissect the complex biological role of NK cells in antitumor responses in vivo, a tumor with well-characterized B- and T-cell responses, Moloney virus-induced sarcoma, will be used. Experiments similar to those with defined antigens will determine whether depletion of NK cells in vivo affects the magnitude and/or kinetics of the Ab response to primary MSV induced sarcoma. Thus, the specific aim of this research is to demonstrate whether or not NK cells directly or indirectly affect B-cell responses and to elucidate the mechanisms of NK-B interactions. The long-term goal is to understand the role of NK cells within the immunoregulatory network. (LB)
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