Weyand, Cornelia

Abstract Immune cell function is tightly coupled to cellular metabolism, with glycolysis, oxidative phosphorylation, and amino acid and lipid metabolism governing activation, differentiation, survival, and effector responses. In rheumatoid arthritis (RA), an autoimmune disease characterized by destructive joint inflammation, metabolic checkpoints have emerged as critical regulators of immune-cell behavior and drivers of tissue pathology. RA CD4+ T cells undergo profound metabolic reprogramming: glycolysis is suppressed, and glucose is redirected into the pentose phosphate pathway, resulting in NADPH accumulation, reduced ROS levels, and a highly reductive intracellular environment. Concurrent defects in mitochondrial DNA repair and electron transport chain function compromise mitochondrial fitness, leading to NAD+ depletion, altered tricarboxylic acid cycle activity, and metabolic exhaustion. The resulting accumulation of citrate and acetyl-CoA promotes lipogenesis and protein acetylation, driving membrane remodeling, tissue invasiveness, and proinflammatory effector functions. Depletion of oxaloacetate and aspartate limits NAD+ regeneration, inducing endoplasmic reticulum expansion and enhanced tumor necrosis factor production. Defective lysosomal coordination of AMPK and mTORC1 signaling uncouples energy sensing from anabolic programs, enabling cellular activation and proliferation despite metabolic insufficiency. Macrophage fate and function are similarly shaped by metabolic state. In synovial macrophages, GLUD1-dependent glutamine oxidation sustains mitochondrial respiration and ATP production, enabling survival under nutrient-deprived conditions while promoting antigen presentation. Conversely, metabolic stress in MerTK+ macrophages activates the NAD+ hydrolase SARM1, triggering NAD+ depletion, mitochondrial collapse, and PANoptotic cell death. Together, these findings identify NAD+ availability, mitochondrial fitness, and organelle-based signaling as central metabolic gatekeepers linking bioenergetic stress to immune-cell dysfunction and chronic inflammation in RA.

The reshaping of the immune system which occurs during aging has detrimental consequences for tissue function and pathology. The August 2025 issue of Nature Aging provides a Focus on immune aging, featuring a series of reviews and opinion pieces on recent advances in immune aging research. This panel discussion hosted by Nature Aging with experts in the field accompanies the Focus issue, and covers emerging concepts in immune aging as well as translational therapies.

Autoimmune vasculitis of the medium and large elastic arteries can cause blindness, stroke, aortic arch syndrome, and aortic aneurysm. The disease is often refractory to immunosuppressive therapy and progresses over decades as smoldering aortitis. How the granulomatous infiltrates in the vessel wall are maintained and how tissue-infiltrating T cells and macrophages are replenished are unknown. Single-cell and whole-tissue transcriptomic studies of immune cell populations in vasculitic arteries identified a CD4 + T cell population with stem cell–like features. CD4 + T cells supplying the tissue-infiltrating and tissue-damaging effector T cells survived in tertiary lymphoid structures around adventitial vasa vasora, expressed the transcription factor T cell factor 1 (TCF1), had high proliferative potential, and gave rise to two effector populations, Eomesodermin (EOMES) + cytotoxic T cells and B cell lymphoma 6 (BCL6) + T follicular helper-like cells. TCF1 hi CD4 + T cells expressing the interleukin 7 receptor (IL-7R) sustained vasculitis in serial transplantation experiments. Thus, TCF1 hi CD4 + T cells function as disease stem cells and promote chronicity and autonomy of autoimmune tissue inflammation. Remission-inducing therapies will require targeting stem-like CD4 + T cells instead of only effector T cells.