| Natural killer (NK) and CD8 T cells are lymphocyte subsets integral in immune responses against viruses. NK cells are part of the innate immune system, and when activated, can proliferate, secrete cytokines, and/or mediate cytotoxicity against susceptible target cells. Although NK cells are activated during virtually every viral infection examined, their contribution to antiviral defense is evident only during certain challenges. In contrast, CD8 T cells, part of the adaptive immune system, are required for effective viral clearance and long-term immunity for nearly all viruses. CD8 T activation also can include cell (clonal) expansion, cytokine secretion, and/or cytotoxicity. These studies were undertaken to examine the role of certain innate factors and their downstream signaling pathways, in particular the cytokines interferons α and β (IFN-α/β and the signal transducer and activator of transcription (STAT) 1 signaling molecule, in orchestrating NK and CD8 T cell responses to viruses. I demonstrate here that IFN-α/β, or type 1 IFNs, are pivotal factors in shaping the endogenous immune response to viral infections. IFN-α/β activate NK cell cytotoxicity and cell cycle entry and indirectly support NK cell expansion and/or survival by induction of another innate cytokine, interleukin (IL-) 15. In addition, type 1 IFNs inhibit NK cell IFN-γ production. In contrast, IFN-α/β promote CD8 T cell IFN-γ expression, and can support memory, but not naive/effector, CD8 T cell proliferation. Interestingly, type I IFNs can have critical roles in regulating CD8 T cell IFN-γ responses. Lastly, IFNs, under conditions of dual viral/bacterial challenges, can drive NK and T cells to mediate pathology. Induction of NK cell cytotoxicity, inhibition of IFN-γ expression, IL-15 induction, and exacerbation of LPS-induced pathology by IFN-α/β all required STAT1, whereas stimulation of IFN-γ expression and memory CD8 T cell proliferation are STAT1 independent. Taken together, the results show that the type 1 IFNs play key roles in immunoregulation of both NK and CD8 T cell responses during viral infections, and can determine the balance between health and disease. Moreover, the multiple, at times paradoxical, IFNα/β-dependent immunoregulatory effects are accessed by these cytokines through the balance of STAT1-dependent or independent signaling pathways. |
