IntroductionCD8 ϩ T cells are critical mediators of adaptive inflammatory responses to intracellular pathogens. They require a series of signals for efficient expansion and acquisition of effector functions, such as cytokine secretion and lytic activity. These signals are delivered by professional antigen-presenting cells (APC) and include antigen recognition (signal 1), costimulatory activation (signal 2), and signaling provided by innate inflammatory cytokines (signal 3). 1 Whereas signals 1 and 2 prime naive CD8 ϩ T cells and initiate cell division, signal 3 cytokines program effector functions and ensure clonal survival. A variety of cytokines have the potential to act as signal 3 in CD4 ϩ and CD8 ϩ T cells, 2-4 and interleukin (IL)-12 and interferon (IFN)-␣/, in particular, promote efficient induction of innate immunity as well as the development of adaptive type 1 responses to intracellular infection. 5,6 Thus, IL-12 and IFN-␣/ may represent the predominant signal 3 during intracellular infection.Whereas IL-12 regulates T helper (Th) 1 development in CD4 ϩ T cells, early reports suggested that the induction of IFN-␥ secretion and lytic activity in CD8 ϩ T cells was independent of IL-12, signal transducer and activator of transcription (STAT) 4, and T-box expressed in T cells (T-bet). [7][8][9] However, recent studies by Schmidt and Mescher found that in vitro priming with IL-12 induced high and sustained secretion of IFN-␥ and markedly enhanced lytic activity in murine CD8 ϩ T cells. 10 Furthermore, these effects were dependent on STAT4, indicating that IL-12 signaling provides a necessary third signal for the regulation of CD8 ϩ T-cell development. 3,11,12 More recent studies have indicated that IFN-␣/ can act in a manner similar to IL-12 to provide signal 3 and promote the induction of cytokine secretion, cytolytic activity, and clonal expansion in murine CD8 ϩ T cells. 3,13 Collectively, these studies suggested that IL-12 and IFN-␣ can act as redundant signals to promote the development of effector responses in murine CD8 ϩ T cells.In addition to enhancing effector cell development, IFN-␣/ was implicated in the generation of memory CD8 ϩ T cells in vivo. In these studies, IFN-␣/ receptor (IFNAR)-deficient, T-cell receptor (TCR)-transgenic (P14) CD8 ϩ T cells failed to expand and generate memory populations in response to in vivo lymphocytic choriomeningitis virus infection despite their ability to proliferate efficiently in vitro. 13 Alternatively, IL-12 Ϫ/Ϫ mice displayed defective primary effector responses, whereas development of T central memory (T CM ) cells was markedly enhanced compared with wild type, indicating that IL-12 signaling suppresses T CM development. [14][15][16] Considering that IFN-␣/ has been implicated in effector and memory cell development, it is unclear how this signal regulates both events and whether any of these activities operate in human CD8 ϩ T cells. Furthermore, it is not clear how IL-12 and IFN-␣/ signals are integrated to balance effector and memory cell develo...
