The goal of this proposal is to understand the mechanisms regulating mouse natural killer (NK) cell proliferation. By the techniques of centrifugal elutriation, sensitivity to a drug specific for dividing cells, and a single-cell cytotoxicity assay which detects lysis mediated by blast-NK cells, I have shown: 1) that interferon (IFN) and IFN inducers stimulate blastogenesis of NK cells in vivo; 2) that the primary lymphoid organ for this blastogenesis is the spleen; and 3) that this blastogenesis is accompanied by increases in turnover rates and numbers of NK cells. I recently have developed an in vitro system to support the proliferation of blast-NK cells elicited by IFN in vivo. The precursors of cells expanding, in this culture system, to mediate lysis of NK sensitive target cells are isolated in equal frequencies from both euthymic and athymic mice. This appears, therefore, to be an excellent model for the characterization of NK cell proliferation. The in vivo and in vitro systems will be combined to study NK cell expansion, the mechanisms of induction and the regulation of NK cell proliferation. Blastogenesis of NK cells will be induced in vivo by stimulation with poly I:C or with purified IFN's ( or ). Further expansion of NK cells will be carried out by multiple stimulations with IFN in vivo and by outgrowth of blast-NK cells in culture. A role for the T cell growth factor, interleukin-2 (IL-2), in the proliferation of NK cells will be determined by quantitating the expression of IL-2 receptors on in vivo elicited blast-NK cells and by growing these blast-NK cells in cloned IL-2. NK cell proliferation in the context of T cell responses will be examined during the infection of euthymic mice with lymphocytic choriomeningitis virus. The information obtained from these studies will be used to expand NK cells and induce antitumor and antiviral states in vivo.
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