Heterogeneity and plasticity of T helper cells

Abstract

CD4 T helper (Th) cells play critical roles in adaptive immune responses. They recruit and activate other immune cells including B cells, CD8 T cells, macrophages, mast cells, neutrophils, eosinophils and basophils. Based on their functions, their pattern of cytokine secretion and their expression of specific transcription factors, Th cells, differentiated from naïve CD4 T cells, are classified into four major lineages, Th1, Th2, Th17 and T regulatory (Treg) cells, although other Th lineages may exist. Subsets of the same lineage may express different effector cytokines, reside at different locations or give rise to cells with different fates, whereas cells from different lineages may secrete common cytokines, such as IL-2, IL-9 and IL-10, resulting in massive heterogeneity of the Th cell population. In addition, the pattern of cytokine secretion may switch from that of one lineage toward another under certain circumstances, suggesting that Th cells are plastic. Tregs are also more heterogeneous and plastic than were originally thought. In this review, we summarize recent reports on heterogeneity and plasticity of Th cells, and discuss potential mechanisms and implications of such features that Th cells display.

Figure 1

T helper lineages and subsets. CD4 T helper cells can be divided into at least four lineages, namely, Th1, Th2, Th17 and Treg. These cells express master transcription factors (shown inside the cells, pSTATs stands for phosphorylated active STATs) and secrete signature cytokines (shown on the top of the cells). Other ‘lineages’, including Th3, Tr1, Tfh and Th9 cells, have been proposed. However, different Tfh cells also produce Th1, Th2, Th17 or Treg cytokines, whereas some Th1, Th2, Th17 and Treg subsets secrete Th9, Tr1 or Th3 ‘signature’ cytokines,IL-9, IL-10 or TGFβ, respectively, as shown by arrows. Therefore, Tfh, Th9, Tr1 and Th3 cells may represent subsets of Th1, Th2, Th17 and Treg lineages.

Figure 2

Plasticity of T helper cells. CD4 T helper cell plasticity depends on the differentiation state and cell types. At early stages of Th differentiation, each lineage can be easily redirected to other directions. However, at later stages, most Th1 and Th2 cells are terminally differentiated and cannot be switched, whereas the majority of Th17 and Treg cells remain plastic throughout their differentiation process.