A bifurcated role for c-Maf in Th2 and Tfh2 cells during helminth infection

Differences in transcriptomes, transcription factor usage, and function have identified T follicular helper 2 (Tfh2) cells and T helper 2 (Th2) cells as distinct CD4 T cell subsets in settings of type-2 inflammation. While the transcriptional programs driving Th2 cell differentiation and cytokine production are well defined, dependence on these classical Th2 programs by Tfh2 cells is less clear. Using cytokine reporter mice in combination with transcription factor inference analysis, the b-Zip transcription factor c-Maf and its targets were identified as an important regulon in both Th2 and Tfh2 cells. Conditional deletion of c-Maf in T cells confirmed its importance in type-2 cytokine expression by Th2 and Tfh2 cells. However, while c-Maf was not required for Th2-driven helminth clearance or lung eosinophilia, it was required for Tfh2-driven IgE production and germinal center formation. This differential regulation of cell mediated and humoral immunity by c-Maf was a result of redundant pathways in Th2 cells that were absent in Tfh2 cells, and c-Maf-specific mechanisms in Tfh2 cells that were absent in Th2 cells. Thus, despite shared expression by Tfh2 and Th2 cells, c-Maf serves as a unique regulator of Tfh2-driven humoral hallmarks during type-2 immunity.