Skip to main content
. 2021 Aug 20;12:694833. doi: 10.3389/fimmu.2021.694833

Figure 1.

Figure 1

Molecular determinants guiding CD4+ T cell differentiation. (A) Th1 development is initiated by IL-12 mediated STAT4 dimerization, driving expression of TBX21. Activation of mTORC1, primarily by CD28, is also required. Maturation occurs in response to IL-12, and to STAT1 activation by autocrine IFN-γ. (B) Th2 differentiation is driven by IL-4, which promotes STAT6-dependent transcription of GATA3, and by mTORC2. (C) Th22 cells form in response to IL-6 driven STAT3 activation, leading to production of AHR. The contributions of mTORC1 and mTORC2 to this process remain unclear. (D) IL-6 in the presence of TGF-b-mediated SMAD activation and strong activation of mTORC1 drives transcription of ROR-yt, which primes cells to acquire a Th17 fate. Maturation occurs downstream of IL-23 mediated STAT3 activation. IL-23 and IL-1b can also promote STAT4-mediated induction of TBX21 in Th17 cells, leading to production of IFN-γ and GM-CSF. (E, F) nTreg cells develop in the thymus following exposure to self-antigen. pTreg cells develop in the periphery in response to foreign antigen. Both require TGF-β and IL-2 to activate SMAD and STAT5 signaling, respectively, which drive transcription of FOXP3. While strong activation of AKT and mTOR favors effector cell development, weak induction favors regulatory cells. (G) Strong TCR stimulation and ICOS ligation by dendritic cells promotes Tfh differentiation. ICOS activates AKT, but also drives STAT3-mediated production of TCF1, which promotes expression of BCL6. Maturation requires continued TCR and ICOS stimulation by B cells. Recently activated cells fated to become Tfh produce IL-2. Signaling is largely paracrine, and drives STAT5 mediated induction of BLIMP1, a mutual antagonist of BCL6, in non-Tfh. (H) Events guiding Tfr differentiation overlap substantially with those of Tfh. Tfr are thought to be derived from FOXP3-positive precursors. As with Tfh, ICOS-mediated STAT3-dependent induction of TCF1 promotes BCL6 expression. However, Tfr appear to depend exclusively on mTORC1, whereas Tfh require both mTORC1 and mTORC2. Similarly, induction of CXCR5 in Tfr appears to require NFAT2, which is dispensable for Tfh development. Created with BioRender.com.