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In contrast to CD4 T cells, CD8 T cells inherently differentiate into IFN-γ-producing effectors. Accordingly, while generation of IFN-γ-producing Th1 CD4 T cells was profoundly impaired in mice deficient for both type-I IFN and IL-12 signaling in response to infection with Listeria monocytogenes, generation of Ag-specific, IFN-γ-producing CD8 T cells was unimpaired. However, a fraction of these CD8 T cells also produced IL-17 in an IL-23-dependent manner. Furthermore, the addition of IL-23 in vitro was sufficient for some naive CD8 T cells to differentiate into IFN-γ/IL-17 dual-producing cells and was associated with increased expression of ROR-γt and ROR-α. Addition of IL-6 and TGF-β to IL-23 further augmented ROR-γt and ROR-α expression and suppressed Eomes expression, thereby enhancing IL-17 production by CD8 T cells. A loss of cytotoxic function accompanied the production of IL-17, as the addition of IL-6 and TGF-β resulted in a marked reduction of granzyme B and perforin expression. Thus, CD8 T cells retain sufficient plasticity to respond to environmental cues and can acquire additional effector functions in response to their environmental context.

It is unknown whether faithful and heritable commitment of CD4 T cells to an effector lineage occurs in vivo or whether plasticity of T cells to adopt different effector functions in vivo is the norm. To address this question, we examined commitment of naïve antigen-specific CD4 T cells generated during intracellular bacterial (Listeria monocytogenes, Lm) or viral (LCMV) infections. The robust TH1-polarizing environment induced by these infections yielded memory CD4 T cells stably committed to the TH1 lineage. The intracellular lifestyle of the microbe and the resultant cytokine milieu induced in response to this lifestyle were key determinants of TH1 fidelity. Infection of wild-type mice with mutant Lm that could not escape the phagocytic vacuole and replicate in the cytosol induced CD4 T cells with a mixed TH1/ TH17 response and decreased effector lineage fidelity, as did infection with wild-type Lm of mice deficient for both IL-12 and type I IFN signaling. Thus, memory CD4 T cells generated in strong TH1-polarizing environments in vivo are strongly committed to this effector lineage. Commitment is highly dependent on innate immune cytokines induced in response to entry into and replication of Lm within the cytosol, and, as we also show, on prior expression of Ifng by these memory T cells. Supported by grants from the NIH and March of Dimes.