Molecular regulation of effector and memory T cell differentiation

Abstract

Immunological memory is a cardinal feature of adaptive immunity and an important goal of vaccination strategies. Here we highlight advances in the understanding of the diverse T lymphocyte subsets that provide acute and long-term protection from infection. These include new insights into the transcription factors, and the upstream 'pioneering' factors that regulate their accessibility to key sites of gene regulation, as well as metabolic regulators that contribute to the differentiation of effector and memory subsets; ontogeny and defining characteristics of tissue-resident memory lymphocytes; and origins of the remarkable heterogeneity exhibited by activated T cells. Collectively, these findings underscore progress in delineating the underlying pathways that control diversification in T cell responses but also reveal gaps in the knowledge, as well as the challenges that arise in the application of this knowledge to rationally elicit desired T cell responses through vaccination and immunotherapy.

Figure 1

Determinants of T lymphocyte fate. (a) Many disparate factors can serve to influence cell-fate specification in the first 24–72 hours following T cell activation; these include TCR signal strength, costimulation, inflammatory cytokines, tissue microenvironment, metabolic regulators and intermediates, ‘pioneering’ and transcription factors and the mode of cellular division (symmetric or asymmetric). It should be emphasized that these inputs are not mutually exclusive and act simultaneously in concert, yielding heterogeneous progeny that continue to integrate cumulative signals. APC, antigen-presenting cell. (b) Categories (top) and prominent examples of each category (below) of factors that can promote ‘effector-like’ or ‘memory-like’ differentiation (left margin). FAO, fatty acid oxidation; SRC, spare respiratory capacity; OxPhos, oxidative phosphorylation.

Figure 2

‘Pioneer’ factors in the establishment of an enhancer ‘landscape’. (a) ‘Pioneer’ transcription factors enter closed chromatin at enhancers and/or promoters of key lineage-specific genes. They displace histones and/or recruit histone-modifying enzymes (such as histone acetyltransferases (HAT)) and other transcription factors. ‘Pioneer’ factors can be either individual transcription factors or complexes. Epigenetically open chromatin at enhancers and promoters then can be acted on by ‘effector’ transcription factors that actively turn gene transcription on and off (in cooperation with other core or generic transcriptional control proteins). Ac, acetylation. (b) In the absence of ‘pioneer’ factor function, an epigenetic ‘landscape’ of accessibility of lineage-specific genes is not established. Effector transcription factors, even if expressed, cannot access lineage-specific genes to regulate expression.

Figure 3

Integration of metabolic state and gene expression. mTOR is activated by environmental cues and signaling via receptors (TCRs, costimulatory receptors and cytokine receptors) in T cells via kinase-dependent pathways, including PI(3)K-Akt and PDK1. mTOR regulates cellular growth, survival and metabolism via multiple mechanisms, including the induction of glycolysis through the stabilization of HIF-1α, as well as lipid and protein biosynthesis. mTOR promotes translation initiation and protein synthesis via phosphorylation of ribosomal protein S6 kinase and eIF4E-binding proteins. The AMPK complex is activated when cellular energy levels decrease (ATP:AMP) and suppresses cell growth by blocking biosynthetic pathways and inhibiting mTOR. AMPK can induce fatty acid oxidation and suppress glycolysis. mTOR can induce activity of HIF, a transcription factor that coordinates the cellular response to low oxygen tension, including induction of the expression of many molecules required for glycolysis. HIF is a heterodimeric complex of either HIF-1α or HIF-2α with HIF-1β, which is constitutively expressed. The stability of HIFa protein is post-transcriptionally regulated by oxygen availability via iron-dependent PHDs, which tag HIF for recognition by ubiquitination dependent on the von Hippel-Lindau tumor suppressor VHL. The stabilization of HIF mRNA and protein in cells of the immune system can be induced by hypoxia as well as by signaling via TCRs, cytokine receptors and Toll-like receptors, whereby it can promote (both directly and indirectly) effector functions, including microbicidal activity by macrophages, cytokine production by T_H17 cells, and expression of effector molecules such as IFN-γ and granzyme B. As an example of a metabolic enzyme that can also function as an RNA-binding protein and regulate mRNA translation, GAPDH has been shown to regulate the translation of mRNA encoding effector molecules such as IFN-γ. GAPDH is engaged as a metabolic enzyme during glycolysis; however, when not engaged in glycolysis and when the cell generates ATP via oxidative phosphorylation, GAPDH can bind the 3′ untranslated region of cytokine-encoding mRNA and diminish translation. Illustrative of how broadly molecules generated by different metabolic pathways may affect gene expression is the activity of products of the TCA cycle. For example, accumulation of α-ketoglutarate, succinate and fumarate produced as part of the TCA cycle can lead to product-mediated inhibition of PHDs and HIF activation and also affect epigenetic modifications of histones and DNA, including decreased methylation. Acetyl-CoA can provide donor acetyl groups that facilitate histone acetylation.