Stimulation of naïve T cells by antigen generates T helper 1 (TH1), TH2, and TH17 effector T cells and inducible regulatory T cells (iTregs) as part of the adaptive immune response. In addition to stimulating T cell differentiation through antigen presentation, co-receptor stimulation, and cytokine production, dendritic cells (DCs) also mediate innate immune signaling by responding to the stimulation of pattern recognition receptors, such as Toll-like receptors (TLRs), by microbial pathogens. Huang et al. investigated how T cell lineage choice was affected by innate immune signaling in DCs by examining T cell responses in mice with DCs deficient in the phosphatase MKP-1, which inhibits the activation of mitogen-activated protein kinases (MAPKs) by TLRs. In the context of bacterial or fungal infection of mice, loss of MKP-1 in DCs resulted in the production of more TH17 cells and less TH1 cells than occurred in mice with wild-type DCs. In vitro co-culture experiments showed that T cells incubated with MKP-1–deficient DCs produced less interferon-γ (IFN-γ, a TH1-associated cytokine) but more interleukin-17 (IL-17, a TH17-associated cytokine) than did T cells incubated with wild-type DCs. In comparison with wild-type DCs, MKP-1–deficient DCs produced more IL-6 (which stimulates TH17 cell differentiation) but less IL-12 (which stimulates TH1 cell differentiation), effects that were blocked by inhibiting p38 MAPK activity. Furthermore, incubation with MKP-1–deficient DCs resulted in altered cytokine receptor profile at the surface of T cells that correlated with the observed alterations in TH1 and TH17 cell differentiation. Finally, the authors showed that MKP-1 in DCs inhibited the generation of iTregs, mostly by inhibiting the production by DCs of the cytokine TGF-β2, which is required to induce iTregs. Together, these data suggest that MKP-1 and p38 signaling in DCs acts as the connection between innate and adaptive immune responses by determining the balance of different T cell fates.
G. Huang, Y. Wang, L. Z. Shi, T.-D. Kanneganti, H. Chi, Signaling by the phosphatase MKP-1 in dendritic cells imprints distinct effector and regulatory T cell fates. Immunity 35, 45–58 (2011). [PubMed]