IL-1β and TGF-β Act Antagonistically in Induction and Differentially in Propagation of Human Proinflammatory Precursor CD4+ T Cells

Cytokines are critical messengers that control the differentiation of Th cells. To evaluate their impact on the fate of human naive CD4(+) T cells from cord and adult blood, early T cell differentiation was monitored after T cell activation in the presence of pro-and anti-inflammatory cytokines. Interestingly, the analysis of Th cell lineage-specific molecules revealed that IL-1 beta on its own mediates differentiation of Th cells that secrete a wide range of proinflammatory cytokines and stably express CD69, STAT1, IFN-gamma, and IL-17. Notably, our data suggest that IL-1 beta induces Th17 cells independent of RORC upregulation. In contrast, TGF-beta that triggers RORC prevents Th17 cell development. This suppressive function of TGF-beta is characterized by inhibition of STAT1, STAT3, and CD69. However, after repeated anti-CD3 and anti-CD28 stimulation, we observe that TGF-beta provokes an increase in Th17 cells that presumably relies on reactivation of a default pathway by preferential inhibition of IFN-gamma. Hence, our data extend the view that the principal cytokines for determining Th cell fate are IL-12 for the Th1 lineage, IL-4 for the Th2 lineage, and TGF-beta in conjunction with IL-6 for the Th17 lineage. We propose that IL-1 beta induces a general proinflammatory Th cell precursor that, in the presence of the lineage-specifying cytokines, further differentiates into one of the specific Th cell sub-populations. The Journal of Immunology, 2011, 187: 5627-5635.