The natural killer (NK) cell system in man is an important component of th immune surveillance network in which a specific subpopulation of lymphocytes can destroy virus-infected cells, tumor cells, and heterologous tissues. Additionally, data have now accrued which indicate that NK cells may also display non-lytic immunoregulatory functions. Recent studies in murine and human systems have shown that populations of lymphocytes containing NK cells can suppress B lymphocyte proliferation and immunoglobulin (lg) production in T cell-dependent systems. However, these studies have not utilized purified populations of NK cells nor have they examined the activity of NK cell subsets. Additionally, there has been no investigation of B cell function in non-T cell-dependent systems. Given the role of NK cells in immunity against tumors and the therapeutic modulation of NK activity with biologic response modifiers such as interferon, it will be extremely important to determine: 1) the interrelationship between NK cell cytotoxic and immunoregulatory function; 2) the modulation of these activities; 3) the regulatory activities of NK cell subsets; 4) the mechanism(s) of regulation; and 5) the NK regulatory function in patients with abnormalities of NK cytotoxic function. To determine these, three specific areas will be investigated. We will ascertain if NK cells can alter B cell function indirectly in T cell-dependent systems. For this, highly purified populations of NK cells will be utilized in pokeweed mitogen-dependent systems of B cell proliferation and lg production. Since all stages in the T cell-independent B cell differentiation sequence can be assessed, we will investigate the ability of NK cells to modulate the early and late steps in this sequence. Given our preliminary data that NK cells can affect B cell function, we will determine the mechanism of this activity (direct vs. indirect; cytoxic vs. non-cytotoxic). These studies will also assess the ability of NK cell subsets to act as modulators of B cell function through the isolation of specific subpopulations of NK cells. Additionally, subsets of NK cells will be isolated by cloning techniques and their ability to affect these responses determined. Lastly, patients with known NK cytotoxic defects (e.f., SLE, AIDS) will be assessed for NK immunoregulatory abnormalities. These studies should increase our knowledge of the roles, significance, and functional capabilities of normal NK cells and the potential importance of these lymphocytes in diseases of immunoregulation.
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