Selective Requirement of p38α MAPK in Cytokine-Dependent, but Not Antigen Receptor-Dependent, Th1 Responses

Abstract

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.

Gadd45α Regulates p38-Dependent Dendritic Cell Cytokine Production and Th1 Differentiation

“…T cell-intrinsic p38 activity has been regarded as crucial for Th1 immune responses, a notion supported by studies with Gadd45␤ Ϫ/Ϫ and Gadd45␥ Ϫ/Ϫ mice (11,12). However, this idea has been challenged by recent observations from chimeric mice expressing p38␣-deficient T cells, in which Th1 polarization is normal (8). Those findings, together with the present observations, suggest that the role of p38 in Th1 polarization is primarily at the level of the DC rather than the T cell.…”

“…Although the p38 inhibitors SB203580 and SC-409 blocked cytokine-mediated IFN-␥ production by Th1 cells, they did not prevent the activation, differentiation, or proliferation of new Th1 cells (5). Recently generated p38␣ Ϫ/Ϫ T and B cells developed and proliferated normally (7), and p38␣-deficient CD4 ϩ T cells differentiated into Th1 effector cells in vitro and expressed normal levels of IFN-␥ when restimulated through the TCR (8), suggesting that T cell p38␣ is dispensable for Th1 development.…”

“…In vitro polarized Th1 cells expressing constitutively active MAP kinase kinase (MKK) 6, an upstream activator of p38, displayed increased IFN-␥ production, whereas expression of a dominant negative form of p38 or treatment with the p38 inhibitor SB203580 decreased IFN-␥ expression by Th1 effectors (4,5). Recently, however, p38␣ Ϫ/Ϫ T and B cells were found to develop normally (7), and p38␣-deficient CD4 ϩ T cells expressed normal levels of IFN-␥ when differentiated in vitro under Th1-polarizing conditions (8). It was also reported that p38 inhibitors blocked cytokine-induced Th1 IFN-␥ production without disrupting the activation and differentiation of new Th1 effector (5).…”

IL-1 family members and STAT activators induce cytokine production by Th2, Th17, and Th1 cells

“…It has also been reported that the affinity of NF-B for the murine Il4 promoter is too weak to be detected (22). In keeping with the requirements for cytokine-stimulated induction of IL-13 and IL-17 in Th2 and Th17 cells, respectively, in Th1 cells, IL-18 plus IL-12-induced IFN␥ production is NF-B and p38 dependent and NFAT independent (10,23,24).…”

p38α MAP kinase‐deficient mouse embryonic stem cells can differentiate to endothelial cells, smooth muscle cells, and neurons

“…Other investigators reported that p38␣Ϫ/Ϫ ESCs were able to differentiate into myeloid-like cells, but that these cells failed to produce IL-6 in response to IL-1 stimulation, as opposed to cells derived from wild type cells (Allen et al, 2000). Similarly, p38␣ was not essential for lymphocyte development (Kim et al, 2005), but p38␣ Ϫ/Ϫ Th1 cells were defective in IFN-␥ secretion stimulated by IL-12/ IL-18 (Berenson et al, 2006). These studies demonstrate the potential of using p38␣ Ϫ/Ϫ ESCs as a genetically defined tool to study this enzyme in the regulation of ESC activities and to provide results that otherwise are not obtainable from studies using fully differentiated adult cells.…”