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NK Cells Regulate CD4 Responses Prior to Antigen Encounter¹

Kennichi C. Dowdell^*, Daniel J. Cua^2,, Erlinda Kirkman and Stephen A. Stohlman^3,*,

Departments of ^* Neurology, Molecular Microbiology and Immunology, and Animal Resources, University of Southern California, Keck School of Medicine, Los Angeles, CA 90033

NK cells not only respond rapidly to infection, shaping subsequent adaptive immunity, but also play a role in regulating autoimmune disease. The ability of NK cells to influence adaptive immunity before Ag exposure was examined in a gender-dependent model of preferential Th1 and Th2 activation. The inability of young adult male SJL mice to activate Th1 cells was reversed via depletion of NK1.1⁺ cells, whereas the presence or the absence of NK1.1⁺ cells did not alter responses in age-matched females. Consistent with a gender-dependent role in regulating adaptive immunity, significantly more NK1.1⁺ cells were present in males compared with females, and this difference was reversed by castration. In contrast to NK1.1⁺ cells derived from C57BL/6 mice, no spontaneous cytokine secretion was detected in NK1.1⁺ cells derived from either male or female SJL mice, although an increased frequency of IL-10-secreting NK1.1⁺ cells was observed in males vs females following in vitro stimulation. Direct evidence that NK1.1⁺ cells in males influence CD4⁺ T cell activation before Ag exposure was demonstrated via the adoptive transfer of APC from control and NK1.1-depleted males. The absence of a functional NK T cell population in SJL mice suggests that NK cells influence adaptive immunity before Ag exposure via alterations in APC activity.

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