Issues in T-helper 1 development--resolved and unresolved

T-helper 1 cell (Th1) development participates in immunity to many pathogens in part by providing a source of interferon (IFN)-gamma that contributes numerous protective effects. The process of Th1 development involves signals provided by antigen-presenting cells and cytokines produced in response to pathogens, with IFN-gamma itself, interleukin (IL)-12, and IL-18 each promoting the process in some way. Despite the rapid progress into mechanisms of Th1 development in recent years, there are still a number of important unresolved issues in this area. The precise sequence of effector and cellular mechanisms represents a relatively recent avenue of research but is still the subject of current debate, as is the basis of mechanisms that may stabilize a Th1 response. Another unresolved issue is the role of type I IFNs in substituting for IL-12-mediated activation of signal transducer and activator of transcription 4 (Stat4) and induction of IFN-gamma in either murine or human T cells. It is now clear that Th1 cells acquire the property of being capable of nonantigen-dependent activation through the coordinate signaling of IL-12 and IL-18, but the precise order of intracellular signaling events and the uniqueness of this pathway's reliance on the p38 mitogen-activated protein kinase (MAPK) pathway are still issues in need of resolution. Finally, the process of verifying the effects of Stat4 mutations on functional responses has led to the recognition of an unexpected action of the STAT N-domain that may apply generally to other STAT proteins as well. None of these areas is static or resolved fully, and they likely will remain topics of rapid progress.