PMC

William E. Paul

Jinfang Zhu

Summary of the 4 CD4 T helper cell fates: their functions, their unique products, their characteristic transcription factors, and cytokines critical for their fate determination.

T-cell differentiation involves instructive differentiation as well as selective expansion of differentiated cells. The cytokines critical for the differentiation of each lineage instruct activated CD4 T cells to express their master transcription factors, T-bet for Th1, GATA-3 for Th2 and RORγt for Th17, as well as other lineage specific factors, IL-12R for Th1, Gfi-1 for Th2 and IL-23R for Th17. In many instances, only a portion of cells expresses the indicated transcription factors and adopts the differentiated phenotype. Such differentiated cells express the factors that determine responsiveness to particular cytokines, IL-12 for Th1, IL-2 for Th2 and IL-23 for Th17 cells, thus leading to selective expansion of those differentiated cells.

Th2 differentiation driven by low concentration of peptide stimulation in vitro consists of an IL-4–independent initiation phase and an IL-4–dependent amplification phase. (A) TCR stimulation by low concentration of peptide induces IL-4–independent GATA-3 expression and IL-2–mediated Stat5 activation. (B) GATA-3 binds to CNS-1 and V_A whereas activated Stat5 binds to HSII and HSIII of Il4 locus. Both are critical for TCR-mediated IL-4 production at the initial phase of Th2 cell differentiation. (C) IL-4 produced by T cells can further induce GATA-3 expression through Stat6 activation. GATA-3 also regulates itself once it reaches a certain threshold. Thus, IL-4–mediated GATA-3 expression together with IL-2–mediated Stat5 activation drives full Th2 differentiation. (D) High levels of GATA-3 and activated Stat5 play critical roles in inducing large amount of IL-4 production.