The signaling symphony: T cell receptor tunes cytokine-mediated T cell differentiation

Abstract

T cell development, differentiation, and maintenance are orchestrated by 2 key signaling axes: the antigen-specific TCR and cytokine-mediated signals. The TCR signals the recognition of self- and foreign antigens to control T cell homeostasis for immune tolerance and immunity, which is regulated by a variety of cytokines to determine T cell subset homeostasis and differentiation. TCR signaling can synergize with or antagonize cytokine-mediated signaling to fine tune T cell fate; however, the latter is less investigated. Murine models with attenuated TCR signaling strength have revealed that TCR signaling can function as regulatory feedback machinery for T cell homeostasis and differentiation in differential cytokine milieus, such as IL-2-mediated Treg development; IL-7-mediated, naïve CD8(+) T cell homeostasis; and IL-4-induced innate memory CD8(+) T cell development. In this review, we discuss the symphonic cross-talk between TCR and cytokine-mediated responses that differentially control T cell behavior, with a focus on the negative tuning by TCR activation on the cytokine effects.

Keywords: effector function; homeostasis; pathway crosstalk; proliferation; signal rheostat.

Figure 1.. TCR tuning of IL-2-mediated T_reg differentiation. Under T_reg differentiation conditions, TGF-β activates transcriptional factors Foxo1/3a to enforce Foxp3 expression, whereas IL-2 activates STAT5, PI3K/Akt/mTOR, and ERK pathways to regulate cell proliferation and metabolism. TCR engagement activates the proximal signalosome involving ITAM/ZAP70/SLP-76/ITK to activate further ERK and PI3K/Akt/mTOR signaling, triggering PTEN turnover and Myc/miR19b-mediated targeting of PTEN to release PI3K/Akt/mTOR signaling from PTEN suppression. Active PI3K/Akt/mTOR is essential for glucose metabolism and can suppress Foxo-mediated Foxp3 expression. Foxp3, in turn, directly suppresses expression of IL-2, ITK, and ZAP70, further regulating PI3K/Akt/mTOR-mediated suppression of Foxp3 expression. Of note, the TCR proximal signalosome can negatively tune IL-2/STAT5 signaling strength, although the details are currently unclear.

Figure 2.. TCR/CD8 coreceptor tuning of IL-7-mediated CD8⁺ T cell homeostasis. IL-7/IL-7R signaling is critical for naïve CD8⁺ T cell homeostasis. IL-7R induces high levels of IFN-γ that induce CICD through auto- and paracrine mechanisms, which counteract the homeostatic proliferation. To prevent CICD, IL-7R activation induces GFI-1-dependent CD8 expression, which potentiates TCR-mediated negative tuning of IL-7R expression and thus, IFN-γ-induced CICD. The IL-7R → CD8 → TCR ⊣ IL-7R negative-feedback loop drives cell-intrinsic IL-7R and TCR oscillatory signaling.

Figure 3.. TCR tuning of IL-4-induced IMP CD8⁺ T cell development. IL-4 drives STAT6-dependent Eomes expression in naïve CD8 SP thymic progenitors, leading to development of the IMP. IL-4 activates PI3K/Akt pathways and drives Eomes translation, likely involving mTOR-mediated translational machinery. TCR signals also activate PI3K/Akt but suppress IL-4R signaling.

Figure 4.. Generalized model for TCR tuning of cytokine-mediated T cell differentiation and homeostasis. γc cytokines (IL-2/IL-4/IL-7) activate the receptor complex and the downstream JAK/STAT and PI3K/Akt signaling pathways. Active STAT can enhance cell proliferation and directly or indirectly modulate expression of effector components, such as cytokines, coreceptor, or TCR signalosome components (e.g., Eomes → IFN-γ, GFI-1 → CD8, Foxp3 ⊣ IL-2/ITK). TCR triggering (with assistance from the coreceptor) suppresses cytokine receptor signaling, likely through modulating receptor complex expression or receptor/JAK/STAT signaling cascade via alternative splicing of RNA, calcium → calpain, PTPs, Dok, SOCS, and/or PIAS. TF, transcription factor.