Since the discovery of Th1 and Th2 cells in the late 1980s, the family of effector CD4(+) helper T (Th) cell subsets has expanded. The differentiation of naïve CD4(+) T cells is largely determined when they interact with dendritic cells (DCs) in lymphoid organs, and cytokines play a major role in the regulation of Th differentiation in the early stages. Recent studies show that the developmental mechanism of certain Th subsets is not fully shared between mice and humans. Here we will review recent discoveries on the roles of cytokines in the regulation of Th differentiation in humans, and discuss the differences between mice and humans in the developmental mechanisms of several Th subsets, including Th17 cells and T follicular helper (Tfh) cells. We propose that the differentiation of human Th subsets is largely regulated by the three cytokines, IL-12, IL-23, and TGF-β.
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