Table 1. Differentiation and function of CD4 effector T cells.

CD4 subset	Figure	Differentiation and function
Th1	1	Stat4 activation upon IL-12 signaling promotes the expression of the master regulator T-bet and the signature cytokine IFNγ. Th1 cells are proinflammatory effector T cells involved in the activation of macrophages and cytotoxic T cells.
Th2	2	Stat6 activation upon IL-4 signaling induces the expression of the master regulator Gata3 and the signature cytokines IL-4, IL-5, and IL-13. Th2 cell effector functions drive immune responses directed against helminths and are central in allergic reactions.
Tfh	3	Tfh cell differentiation involves multiple cell–cell interactions that are spatially and temporally defined. Stat3 activation upon IL-6 signaling triggers the expression of the master regulator Bcl6. Tfh cells provide help to B cells through direct cell–cell interactions and release of different cytokines (e.g., IL-21 at first and subsequently IL-4, IL-17, or IFNγ). Their effector function is critical for controlling the development of humoral immunity and the generation of high-affinity antibodies.
Th17	4	Stat3 activation in the context of IL-6 and TGFβ signaling promotes the expression of the master regulator Rorγt and the signature cytokine IL-17. Th17 effector functions are proinflammatory and protect epithelial barriers of the gastrointestinal tract, the respiratory tract, and the skin from bacterial and fungal infections.
iTreg	5	Stat5 activation upon IL-2 signaling as well as TGFβ-dependent Smad signaling lead to the expression of the master regulator Foxp3. Treg cells suppress effector functions of other T cells through a variety of mechanisms, including IL-10 and TGFβ production, thereby limiting tissue damage and other inflammatory effects of acute or chronic immune responses.

Differentiation of CD4 T helper cell subsets can be described in a simplified scheme (Figs. 1, 2, 3, 4, and 5; O’Shea and Paul, 2010). Activation, proliferation, survival, and differentiation are induced by TCR and costimulatory receptor signaling. Additional engagement of cytokines with their receptors activates Stat proteins. Differential activation of Stats controls the expression of subset-specifying transcription factors, which in turn induce additional differentiation-associated genes, including those of signature cytokines.