CD4 T cells: fates, functions, and faults

Abstract

In 1986, Mosmann and Coffman identified 2 subsets of activated CD4 T cells, Th1 and Th2 cells, which differed from each other in their pattern of cytokine production and their functions. Our understanding of the importance of the distinct differentiated forms of CD4 T cells and of the mechanisms through which they achieve their differentiated state has greatly expanded over the past 2 decades. Today at least 4 distinct CD4 T-cell subsets have been shown to exist, Th1, Th2, Th17, and iTreg cells. Here we summarize much of what is known about the 4 subsets, including the history of their discovery, their unique cytokine products and related functions, their distinctive expression of cell surface receptors and their characteristic transcription factors, the regulation of their fate determination, and the consequences of their abnormal activation.

Jinfang Zhu

William E. Paul

Figure 1

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.

Figure 2

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.

Figure 3

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.

Figure 4

Cross regulation among the factors that are involved in Th1 and Th2 differentiation.

Figure 5

Positive and negative regulatory elements within Il4/Il13 loci and their binding to transcription factors.