Metabolic reprogramming in inflammaging and aging in T cells

Aging represents an emerging challenge for public health due to the declined immune responses against pathogens, weakened vaccination efficacy, and disturbed tissue homeostasis. Metabolic alterations in cellular and systemic levels are also known to be cardinal features of aging. Moreover, cellular metabolism has emerged to provide regulations to guide immune cell behavior via modulations on signaling cascades and epigenetic landscape, and the aberrant aging process in immune cells can lead to inflammaging, a chronic and low-grade inflammation that facilitates aging by perturbing homeostasis in tissues and organs. Here, we review how the metabolic program in T cells is influenced by the aging process and how aged T cells modulate inflammaging. In addition, we discuss the potential approaches to reverse or ameliorate aging by rewiring the metabolic programming of immune cells.

A review collection on immunometabolism

Recent studies indicate an intimate link between immunity and metabolism,spawning the now burgeoning field of immunometabolism.What is the rationale for such a link?On the one hand,immune responses are energetically very demanding.Clonal expansion of T and B cells,increased production of inflammatory cytokines and antibodies by activated macrophages and plasma cells,and recruitment of immune cells to the site of infection are all thought to impose a high metabolic and energetic demand.This may explain why cellular metabolism regulates the activation/differentiation and proliferation of T and B cells.

Enforced PGC-1α expression promotes CD8 T cell fitness, memory formation and antitumor immunity

Memory CD8 T cells can provide long-term protection against tumors,which depends on their enhanced proliferative capacity,self-renewal and unique metabolic rewiring to sustain cellular fitness.Specifically,memory CD8 T cells engage oxidative phosphorylation and fatty acid oxidation to fulfill their metabolic demands.In contrast,tumor-infiltrating lymphocytes(TILs)display severe metabolic defects,which may underlie their functional decline.Here,we show that overexpression of proliferator-activated receptor gamma coactivator 1-alpha(PGC-1α),the master regulator of mitochondrial biogenesis(MB),favors CD8 T cell central memory formation rather than resident memory generation.PGC-1α-overexpressing CD8 T cells persist and mediate more robust recall responses to bacterial infection or peptide vaccination.Importantly,CD8 T cells with enhanced PGC-1αexpression provide stronger antitumor immunity in a mouse melanoma model.Moreover,TILs overexpressing PGC-1αmaintain higher mitochondrial activity and improved expansion when rechallenged in a tumor-free host.Altogether,our findings indicate that enforcing mitochondrial biogenesis promotes CD8 T cell memory formation,metabolic fitness,and antitumor immunity in vivo.

Metabolic programming in dendritic cells tailors immune responses and homeostasis

It is being increasingly acknowledged that immune cells depend on certain metabolic traits to perform their functions and that the extracellular environment can influence cell metabolism and vice versa.Dendritic cell(DC)subsets traffic through highly diverse environments from the bone marrow,where they develop,to the various peripheral tissues,where they differentiate and capture antigens,before they migrate to the lymph node to present antigens and prime T cells.It is plausible that DC subsets modulate their stimulatory abilities in response to unique metabolic programming.The metabolic requirements of DCs are just recently being discovered,and subset-and context-specific metabolic phenotypes in DCs are highly intertwined with DC functions.In this review,we present the current knowledge on the intrinsic and extrinsic determinants of DC metabolism,how they regulate DC function with examples from tumor biology and in interaction with the microbiota,and discuss how this can be applied therapeutically.