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.
The role of the p38 MAPK pathway in Th1 development has been controversial, because indirect manipulations of either upstream p38 activators or modifiers of p38 activity have had variable effects on IFN-γ production in CD4+ T cells. Uncertainties regarding the specificity of pharmacologic inhibition or p38 dominant negative mutants diminish the strength of conclusions about the role of the p38α isoform in Th1 development. Also, the effects of some upstream p38 activators, such as MAPK kinase 3, on Th1 development are not as strong as the effects of other manipulations, such as the expression of a dominant negative p38 mutant. Finally, embryonic lethality has prevented a direct examination of p38α-deficient T cells. To test the requirement for p38α in Th1 differentiation, we generated Ag-specific p38α+/− and p38α−/− CD4+ T cells using RAG2−/− blastocyst complementation and retroviral expression of the DO11.10 TCR. IFN-γ production in response to TCR signaling is normal in p38α−/− T cells cultured in Th1 conditions, implying normal Th1 development. However, p38α−/− Th1 cells have a much greater defect in IFN-γ secretion stimulated by IL-12/IL-18 compared with TCR-induced IFN-γ secretion. These results suggest that the activity of p38α in Th1 cells is relatively restricted to acting in one of two alternative pathways (i.e., cytokine induced) that can induce the production of IFN-γ in differentiated Th1 cells, but that p38α is not required for the process of Th1 commitment and development itself.
We previously reported that IL-12, but not IFN-aA/D, induces T helper type (Th) 1 development and STAT4 phosphorylation in murine CD4 + T cells. However, a recent study reported that IFN-aA/D and recombinant murine IFN-aA can induce STAT4 phosphorylation, although more weakly than IL-12, largely in CD8 + rather than CD4 + T cells. That report did not examine Th1 development or directly demonstrate induction of IFN-c by IFN-a. To address these differences, we compared IFN-aA/D, murine IFN-aA, and IL-12 for STAT4 phosphorylation, formation of active nuclear DNA binding complexes, induction of Th1 development, and production of IFN-c in murine CD4 + T cells. IFN-aA induced detectable STAT4 phosphorylation, although at significantly lower levels than induced by IL-12. Furthermore, in contrast to IL-12, IFN-aA failed to induce Th1 development or the formation of DNA binding complexes or to synergize with IL-18 for induction of IFN-c production. STAT1-deficient CD4 + T cells showed increased IFN-aA-induced STAT4 phosphorylation but still exhibited significantly lower amounts of cytokine-induced IFN-c compared to IL-12. In summary, these results suggest that in contrast to IL-12, IFN-aA does not play a functionally significant role in meditating the STAT4-dependent induction of Th1 development or IFN-c production in CD4 + T cells.
The role of type I IFN in Th1 development, STAT4 activation, and IFN-γ production in murine T cells has remained unresolved despite extensive examination. Initial studies indicated that IFN-α induced Th1 development and IFN-γ production in human, but not murine, T cells, suggesting species-specific differences in signaling. Later studies suggested that IFN-α also induced Th1 development in mice, similar to IL-12. More recent studies have questioned whether IFN-α actually induces Th1 development even in the human system. In the present study, we compared the capacity of IL-12 and IFN-α to induce Th1 differentiation, STAT4 phosphorylation, and IFN-γ production in murine T cells. First, we show that IFN-α, in contrast to IL-12, cannot induce Th1 development. However, in differentiated Th1 cells, IFN-α can induce transient, but not sustained, STAT4 phosphorylation and, in synergy with IL-18, can induce transient, but not sustained, IFN-γ production in Th1 cells, in contrast to the sustained actions of IL-12. Furthermore, loss of STAT1 increases IFN-α-induced STAT4 phosphorylation, but does not generate levels of STAT4 activation or IFN-γ production achieved by IL-12 or convert transient STAT4 activation into a sustained response. Our findings agree with recent observations in human T cells that IFN-α-induced STAT4 activation is transient and unable to induce Th1 development, and indicate that IFN-α may act similarly in human and murine T cells.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.