IL-21 and T Cell Differentiation: Consider the Context

Accumulating studies demonstrate that IL-21 modulates the differentiation of various CD4 and CD8 T cell subsets and provide insights into the underlying cellular and molecular processes that are influenced by this cytokine. Intriguingly, the effects of IL-21 on T cells can be complex and vary depending on the experimental system used. We review our current understanding of the roles of IL-21 in the generation of phenotypically distinct CD4 and CD8 T cell populations and discuss the potential environmental cues, cellular factors, and molecular mediators that impact the actions of IL-21. We propose that IL-21 acts in a context-dependent manner to accentuate T cell subset development.

TrendsIL-21 accentuates the differentiation of multiple CD4 and CD8 T cell subsets, including the more recently characterized Th9, Tfr, and IL-22-producing CD4 T cell populations and also possibly CD8 Trm cells.Emerging evidence suggests that the effects of IL-21 on T cell differentiation are context dependent and vary with the infection, inflammation, and cytokine milieu. Certain cytokines, such as IL-6 and IL-10, as well as antigenic signals may compensate for IL-21 under certain circumstances.The reciprocal balance between STAT1 and STAT3 is important in dictating the outcome of IL-21 signaling and the expression of IL-21-associated genes.The function of IL-21 in CD8 T cells is especially prominent during chronic viral infections. IL-21 sustains CD8 T cells in chronically infected hosts in part by upregulating the expression of the transcription factor BATF.