Integrating canonical and metabolic signalling programmes in the regulation of T cell responses

Abstract

Over the past decade, our understanding of T cell activation, differentiation and function has markedly expanded, providing a greater appreciation of the signals and pathways that regulate these processes. It has become clear that evolutionarily conserved pathways that regulate stress responses, metabolism, autophagy and survival have crucial and specific roles in regulating T cell responses. Recent studies suggest that the metabolic pathways involving MYC, hypoxia-inducible factor 1α (HIF1α), AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) are activated upon antigen recognition and that they are required for directing the consequences of T cell receptor engagement. The purpose of this Review is to provide an integrated view of the role of these metabolic pathways and of canonical T cell signalling pathways in regulating the outcome of T cell responses.

Figure 1. Canonical T cell signalling pathways: signal 1 and signal 2

a | Signal 1 (T cell receptor (TCR) engagement) in the setting of signal 2 (co-stimulation; depicted as CD28) leads to full T cell activation. This is facilitated by the activation of three canonical transcription factors — nuclear factor-κB (NF-κB), activator protein 1 (AP-1) and nuclear factor of activated T cells (NFAT)^,,,. This, in turn, leads to the expression of multiple cytokines, chemokines and cell surface receptors, all of which promote T cell activation and proliferation. Alternatively, TCR recognition alone (in the absence of co-stimulation) leads to an ‘off’ signal in the form of T cell anergy^,. Under these conditions, NFAT is activated in the absence of full AP-1 activation, which leads to the expression of genes such as diacylglycerol kinase-α (DGKA) and the E3 ubiquitin-protein ligases CBLB and GRAIL (which encodes gene related to anergy in lymphocytes; also known as RNF128), which inhibit full T cell activation. b | Upon T cell activation, cytokines in the T cell microenvironment determine the outcome of antigen recognition with regard to effector T cell differentiation. As shown for CD4⁺ T cells, interleukin-12 (IL-12), IL-4 and IL-6 activate signal transducer and activator of transcription 4 (STAT4), STAT6 and STAT3, respectively. This leads to the expression of T-bet, GATA-binding protein 3 (GATA3) and retinoic acid receptor-related orphan receptor-γt (RORγt), which facilitates the generation of T helper 1 (T_H1), T_H2 and T_H17 cells. Alternatively, transforming growth factor-β (TGFβ) signalling through SMAD2-SMAD4 promotes the expression of forkhead box P3 (FOXP3) and the generation of regulatory T (T_Reg) cells. DAG, diacylglycerol; IKK, inhibitor of NF-κB kinase; InsP₃, inositol-1,4,5-trisphosphate; LAT, linker for activation of T cells; MAPK, mitogen-activated protein kinase; MAPKK, MAPK kinase; PI3K, phosphoinositide 3-kinase; PKCθ, protein kinase Cθ; PLCγ, phospholipase Cγ; PtdInsP₂, phosphatidylinositol-4,5-bisphosphate; SLP76, SH2 domain-containing leukocyte protein of 76 kDa (also known as LCP2); ZAP70, ζ-chain-associated protein kinase of 70 kDa.

Figure 2. Integrating immunological and metabolic signalling programmes to promote effector T cell generation and function

The figure shows the coordinated integration of canonical T cell signalling (blue) and metabolic regulators (green) to promote the generation and function of effector T cells. In this perspective, hypoxia-inducible factor 1α (HIF1α) and MYC are just as integral to T cell effector generation as nuclear factor of activated T cells (NFAT), activator protein 1 (AP-1) and nuclear factor-κB (NF-κB). Similarly, mammalian target of rapamycin (mTOR) signalling is as crucial in effector T cell activation and differentiation as the activation of mitogen-activated protein kinase (MAPK), protein kinase Cθ (PKCθ) and calcineurin. Thicker arrows indicate the activation of metabolic programmes. Thinner arrows indicate signalling cascades. DAG, diacylglycerol; FOXP3, forkhead box P3; GLUT, glucose transporter; IKK, inhibitor of NF-κB kinase; IL-6R, interleukin-6 receptor; InsP₃, inositol-1,4,5-trisphosphate; LAT, linker for activation of T cells; MAPKK, MAPK kinase; PI3K, phosphoinositide 3-kinase; PKCθ, protein kinase Cθ; PLCγ, phospholipase Cγ; PtdInsP₂, phosphatidylinositol-4,5-bisphosphate; SLP76, SH2 domain-containing leukocyte protein of 76 kDa (also known as LCP2); STAT, signal transducer and activator of transcription; TCR, T cell receptor; T_H cell, T helper cell; ZAP70, ζ-chain-associated protein kinase of 70 kDa.

Figure 3. Integrating immunological and metabolic signalling programmes to promote CD8⁺ memory and CD4⁺ regulatory T cell generation

This figure depicts the integration of the canonical T cell signalling pathways (blue) and metabolic regulators (green for activated and red for inhibited). AMP-activated protein kinase (AMPK) activation promotes metabolic programmes that enhance the generation of memory and regulatory T (T_Reg) cells. Alternatively, it is the inhibition of mammalian target of rapamycin (mTOR) and hypoxia-inducible factor 1α (HIF1α) activation that promotes the generation of CD8⁺ memory or CD4⁺ regulatory T_Reg cells. From this perspective, memory T cells and T_Reg cells share similar metabolic requirements. Thicker arrows indicate the downstream consequences of AMPK activation, and of the inhibition of mTOR and HIF1α. AP-1, activator protein 1; DAG, diacylglycerol; FOXP3, forkhead box P3; IKK, inhibitor of NF-κB kinase; InsP₃, inositol-1,4,5-trisphosphate; LAT, linker for activation of T cells; LKB1, liver kinase B1; MAPK, mitogen-activated protein kinase; MAPKK, MAPK kinase; NFAT, nuclear factor of activated T cells; NF-κB, nuclear factor-κB; PI3K, phosphoinositide 3-kinase; PKCθ, protein kinase Cθ; PLCγ, phospholipase Cγ; PtdInsP₂, phosphatidylinositol-4,5-bisphosphate; SLP76, SH2 domain-containing leukocyte protein of 76 kDa (also known as LCP2); TCR, T cell receptor; T_H cell, T helper cell; ZAP70, ζ-chain-associated protein kinase of 70 kDa.