Metabolic adaptation of lymphocytes in immunity and disease

Abstract

Adaptive immune responses mediated by T cells and B cells are crucial for protective immunity against pathogens and tumors. Differentiation and function of immune cells require dynamic reprogramming of cellular metabolism. Metabolic inputs, pathways, and enzymes display remarkable flexibility and heterogeneity, especially in vivo. How metabolic plasticity and adaptation dictate functional specialization of immune cells is fundamental to our understanding and therapeutic modulation of the immune system. Extensive progress has been made in characterizing the effects of metabolic networks on immune cell fate and function in discrete microenvironments or immunological contexts. In this review, we summarize how rewiring of cellular metabolism determines the outcome of adaptive immunity in vivo, with a focus on how metabolites, nutrients, and driver genes in immunometabolism instruct cellular programming and immune responses during infection, inflammation, and cancer in mice and humans. Understanding context-dependent metabolic remodeling will manifest legitimate opportunities for therapeutic intervention of human disease. ll

Divide and Conquer: Phenotypic and Temporal Heterogeneity Within CD8+ T Cell Responses

“…In addition to direct effects on metabolic pathways, proteomics experiments revealed that IL2 also affected the metabolism of in vitro-derived effector CTLs by controlling expression of nutrient transporters and other environmental sensors (122). Given that metabolic shifts during T cell activation are strongly associated with differentiation outcomes (123), these data suggest a mechanism by which differences in the local cytokine and costimulatory environment during activation might propagate through divergent differentiation fates.…”

Ketolysis is a metabolic driver of CD8+ T cell effector function through histone acetylation

“…Central to host defense are CD8 + T cells, which are critical for pathogen clearance and protecting the host from re-infection through long-lived immune memory ( 1, 2 ). One of the fundamental biological programs supporting T cell effector function is cellular metabolism, which generates energy and biosynthetic precursors essential for CD8 + T effector (Teff) cell proliferation, survival, and production of effector molecules (i.e., IFN-γ, TNF-α, and cytolytic factors) ( 3–5 ). CD8 + Teff cells undergo extensive metabolic rewiring to arm themselves with the bioenergetic and biosynthetic capacity to successfully protect the host ( 6, 7 ).…”

“…2a ). CD8 + T cells display plasticity in metabolic fuel choice, which allows them to operate and maintain effector function in diverse metabolic environments ( 5 ). To compare the contribution of KB-derived carbon with other carbon sources for TCA cycle metabolism, we cultured CD8 + Teff cells in the presence of 13 C-labelled substrates at concentrations commonly observed in plasma ( 38, 39 ) and assessed contribution to TCA cycle-derived metabolites.…”

A central role for STAT5 in the transcriptional programing of T helper cell metabolism

“…Upon engagement of the T cell receptor (TCR) and costimulatory receptors, CD4 + T H cells escalate their metabolism to support clonal expansion and energetically demanding effector functions ( 1 ). Nutrient uptake and protein and lipid synthesis are massively induced, and energy production is both augmented and diversified ( 2 , 3 ). Effector T cells (T eff ) get much of their energy from oxidative phosphorylation (OxPhos), a process aided by increased mitochondrial mass and enhanced mitochondria function after activation ( 4 ).…”