IL-21 and T Cell Differentiation: Consider the Context

Abstract

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.

Figure 1

IL-21 modulates the differentiation of CD4 and CD8 T cell subsets in a context-dependent manner. (A) IL-21 suppresses the differentiation of several CD4 T cell subsets including Th1, Th9, regulatory T (Treg), and follicular regulatory T (Tfr) cells, while it promotes the differentiation of IL-22-producing CD4 T cells as well as type 1 regulatory T (Tr1), Th2, Th17, and follicular helper T (Tfh) cells. However, the roles of IL-21 in Th2, Th17 and Tfh cell differentiation may vary between different disease models. (B) IL-21 has been reported to promote the development of memory precursor cells (MPCs) (in conjunction with IL-10), terminal effector cells (TECs), central memory T (Tcm), effector memory T (Tem), and tissue-resident memory T (Trm) cells, and is stringently required to alleviate exhausted T cell (Tex) responses during chronic LCMV infections. Dashed lines indicate that conflicting results have been reported regarding the function of IL-21 in the differentiation of the indicated T cell populations. Abbreviations: AhR, aryl hydrocarbon receptor; BATF, basic leucine transcription factor ATF-like; Bcl6, B cell lymphoma 6; CTLA4, cytotoxic T-lymphocyte associated antigen 4; Eomes, Eomesodermin; Foxp3, forkhead box P3; GITR, glucocorticoid-induced TNF receptor family related protein; ICOS, inducible costimulatory receptor; IFNγ, interferon- γ; KLRG1, killer cell lectin-like receptor G1; ROR-γt, retinoic acid receptor-related orphan receptor (ROR)-γt; SOCS, suppressor of cytokine signaling; STAT4, signal transducer and activator of transcription 4; TGFβ1, transforming growth factor β1.

Figure 2

The reciprocal balance between STAT1 and STAT3 influences the expression of IL-21-regulated genes in CD4 T cells. IL-21 activates both STAT1 and STAT3, which can differentially regulate gene expression and counteract each other. Additionally, IL-21 has also been shown to impact STAT4 and STAT5 activities. STAT3 induces SOCS1 and SOCS3, as well as the expression of IL-21-driven genes including IL-21 itself. Conversely, the expression of STAT1-regulated genes such as T-bet and interferon- γ (IFNγ) is further elevated in IL-21 activated CD4 T cells by the absence of STAT3. Thus, the actions of IL-21 may depend on the relative expression and activity of STAT1 and STAT3. Since the binding of STAT3 to many of its target sites relies on IRF4, other transcription factors also influence the interpretation of IL-21 signals. Notably, IL-21 also leverages the expression of other transcription regulators that control T cell fate decisions and lineage fitness including B cell lymphoma 6 (Bcl6), B lymphocyte-induced maturation protein-1 (Blimp1), eomesodermin (Eomes), T cell factor-1 (TCF-1) and lymphoid enhancer-binding factor-1 (LEF-1). Abbreviations: IRF4, interferon regulatory factor 4; SOCS, suppressor of cytokine signaling; STAT, signal transducer and activator of transcription; TFs, transcription factors.

Figure 3

The actions of IL-21 on T cells are context-dependent and shaped by cellular and environmental parameters. IL-21 signals are interpreted and integrated via a network that includes STAT, MAPK, and PI3K-AKT transduction pathways. STAT proteins are central constituents of this network, and a wide array of cytokines including IL-6, IL-10, IL-2, IL-7 as well as IL-15 activate overlapping and distinct STAT proteins that cooperate with, counteract, or compensate for IL-21. Suppressor of cytokine signaling (SOCS) proteins, which attenuate STAT activation also provide an additional level of regulation. IL-21 may integrate with TCR-signals via the PI3K-AKT pathway which can culminate in the activation of mammalian target of rapamycin (mTOR), which is also sensitive to nutrient levels and plays important roles in T cell metabolism and differentiation. In addition, mTOR has been shown in CD8 T cells to promote the expression of interferon regulatory factor 4 (IRF4), which is necessary for STAT3 binding to many of its target sties. IL-21 can also promote proliferative responses by activation of MAPK. Thus, antigenic signals, other cytokines, and the metabolic status of the responding cell all likely contribute to the eventual outcome of IL-21 signaling. Finally, the epigenetic profiles of target genes and the binding of transcriptional regulators may mutually influence each other, adding to the cell-type dependent control of the magnitude and patterns of gene expression that dictate the differentiation, plasticity, and survival of the responding cells. Abbreviations: MAPK, mitogen-activated protein kinase; MHC, major histocompatibility complex; PI3K, phosphoinositide 3- kinase; RAGs, RAS-related GTP-binding protein family of small GTPases; STAT, signal transducer and activator of transcription; TCR, T cell receptor.