Metabolic regulation of tissue-resident memory CD8+ T cells

Abstract

Intracellular metabolic adaptations help define the function and homeostasis of memory CD8⁺ T cells. These cells, which promote protection against infections or cancer, undergo consecutive metabolic shifts, ultimately relying on mitochondrial-related pathways. Past CD8⁺ T cell metabolism studies focused on circulating memory cells, which are exclusive to secondary lymphoid organs or recirculate between lymphoid and non-lymphoid organs. Yet, now there is unequivocal evidence that memory CD8⁺ T cells reside in many non-lymphoid organs and mediate protective immunity in barrier tissues. The metabolic adaptations occurring in forming and established tissue-resident memory CD8⁺ T cells are currently subject of intense research. In this review, we discuss the latest breakthroughs on the transcriptional and protein control of tissue-resident memory CD8⁺ T cell metabolism.

Keywords: Bhlhe40; Memory CD8(+) T cells; Memory precursor; Mitochondria; P2RX7; T(RM) cells.

Figure 1.. Bhlhe40 as a T_RM metabolic regulator.

Bhlhe40 expression promotes the up-regulation of T_RM-associated transcription factors like Runx3 and Notch1/2, and concomitantly is crucial for the engagement of the TCA/OXPHOS pathway, thus favoring mitochondrial function in T_RM. Consequently, Bhlhe40⁺ T_RM display enhanced mitochondrial fitness, effector function and ability to establish residency long-term. Unveiling a) which upstream factors support Bhlhe40 expression, with special attention to TGF-β, and b) whether Bhlhe40 specifically directs the formation of Blimp1⁺ effector-like T_RM are subjects for future research.

Figure 2.. T_RM metabolism control by extracellular factors.

The T_RM mitochondrial metabolism is somewhat similar to that observed for circulating T_CM. Both subsets are long-lived and rely on mitochondrial respiration via FAO for their homeostasis. Unlike T_CM, which synthetize fatty acids through varied mechanisms, T_RM mainly use exogenous fatty acids, internalized by FABP molecules (FABP4/5 in skin T_RM). T_CM and T_RM also rely on P2RX7-mediated eATP sensing that controls their mitochondrial function and their long-term survival. In the case of T_RM, P2RX7 action in mitochondria is to some extent intertwined with signals promoted by TGF-β. Defining how these signaling pathways are connected to promote T_RM mitochondrial homeostasis will be determined in future studies.