Citations

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.

TRAIL is a TNF family ligand that trimerizes TRAIL-R1 (DR4) or TRAIL-R2 (DR5) to induce apoptosis, necroptosis, and/or NF-κB activation in receptor-bearing cells. We previously identified TRAILshort as a splice variant of TRAIL that lacks cysteine 230, cannot trimerize, and acts as a dominant-negative ligand that blocks TRAIL-mediated apoptosis. TRAILshort is expressed on cell surfaces and within extracellular vesicles, enabling it to confer TRAIL resistance to both producing and bystander cells. In this study, we showed that elevated TRAILshort levels were associated with chronic viral infections, cancer, and autoimmune diseases, suggesting a link to impaired immune regulation. Using unbiased phosphoproteomics and mechanistic studies, we demonstrated that TRAILshort binding to DR5 recruited and activated the phosphatase Src homology region 2 domain–containing phosphatase 1 (SHP-1), leading to zeta-chain-associated protein kinase 70 (ZAP-70) dephosphorylation, disruption of ZAP-70–CD3ζ interactions, and impaired T cell receptor signaling, thereby reducing T cell activation, proliferation, and cytokine production in response to antigen or CD3/CD28 ligation. Genetic or pharmacologic SHP-1 inhibition reverses these effects. In humanized mouse models, TRAILshort promoted the persistence of transformed mouse embryonic fibroblasts (MEFs) and L428 and antagonized CD19-directed CAR T cell activity, revealing TRAILshort as an immunomodulator of T cell function with therapeutic implications, including blocking TRAILshort to restore T cell immunity or delivering TRAILshort to enforce tolerance. TRAILshort, a variant of TRAIL, suppresses T cell function and immune responses in cancer and infectious diseases, highlighting its potential as a therapeutic target.

Abstract Introduction The ability of the adaptive immune system to have memory of previous pathogen encounters is the basis for vaccination as one of the most successful medical interventions. With increasing age, the ability to develop protective immunity after vaccination declines. Differentiation into T memory cells is at least in part determined during the early cell divisions after activation when cells undergo assymmetric cell division (ACD). Fate decisions depend on the uneven distribution of signaling molecules and transcription factors with accumulation of mTORC1 activity biasing for an effector and TCF1 for a memory state. We explored whether ACD of naïve CD4 T cells is impaired in older adults. Methods We used human primary cells from young and older adults. Human naive CD4 T cells were isolated and cultured in RPMI, 10% FBS and antibiotics on plates coated with anti-CD3 Ab, anti-CD28 Ab and huICAM1 for 3 days. We used transfection by electroporation to modify gene expression. Read out systems included confocal microscopy, flow cytometry and lysosome function assays. Results were compared by t-test with values of p < 0.05 considered significant. Results Naive CD4 T cell responses from older adults is characterized by increased activation of the AKT-mTORC1 pathway and reduced ACD of mTORC1 activity. Increased RICTOR expression resulting in increased mTORC2 activity in naive CD4 T cells from older individuals accounted for the activation of the AKT-mTORC1 pathway. AKT inhibition or silencing of RICTOR restores ACD of mTORC1 activity as well as of TCF1. Conversely, ACD was also improved through inducing WNT signaling by GSK3β inhibition irrespective of RICTOR expression. Conclusion Our data show that increased RICTOR expression in naïve T cells from older adults at least in part accounts for defective memory cell generation. Silencing of RICTOR or downstream AKT inhibition can enforce both mTORC1 ACD and TCF1 ACD suggesting that mTORC2 is a promising target to improve vaccine responses. Funding Source n/a Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)

Introduction: V-domain Immunoglobulin Suppressor of T-cell Activation (VISTA), a co-inhibitory immune checkpoint protein, is known for regulating adaptive immune responses. Here, we investigated the role of VISTA in atherosclerosis. Hypothesis: VISTA is constitutively expressed on hematopoietic cells, particularly T cells. VISTA functions as both a ligand and receptor to maintain T cell quiescence. We hypothesize that VISTA expression is protective against plaque formation by inhibiting CD4 + T cell activation. Methods: Cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) was performed on aortic CD45 + cells of HCD fed ApoE-/- mice. Spatial transcriptomics (VISIUM) was performed on carotid plaques from patients with either asymptomatic or symptomatic cerebrovascular disease. Plaque burden, characterization, and flow cytometry of blood and lymphoid organs were performed on VISTA -/- ApoE -/- (VISTA KO) and VISTA +/+ ApoE -/- (WT) mice that were fed a HCD for 10 weeks. ApoE -/- mice treated with VISTA agonist 8G8 or IgG control (200ug, intra-peritoneal, 3 times per week for the last 6/10 weeks of HCD feeding). In vitro proliferation, migration, and functional T cell assays were performed. Results: We found that VISTA is expressed on plaque T cell populations, particularly regulatory T cells, gamma-delta T cells, and naïve T cells. In humans, individuals with symptomatic CVD have significantly reduced VISTA gene expression in carotid plaques. VISTA KO mice have increased total plaque area and necrotic core area compared to littermate WT controls. VISTA KO mice have increased peripheral CD4 + and CD8 + effector memory T (T EM ) cells with a corresponding decrease in CD4 + and CD8 + naïve T (T N ) cells and CD4 + regulatory T (T reg ) cells. Further, VISTA KO mice have a higher frequency of CD4 + T H 1 (T-bet + IFNy + ) cells and lower frequencies of IL-10 + CD4 + T cells and CD4 + T H 2 (GATA-3 + IL-13 + ) cells. In vitro assays showed that VISTA suppresses CD4 + T cell proliferation, IFNγ production, and migration. Finally, VISTA agonist treatment significantly decreased plaque and necrotic core areas in atherosclerotic mice. Conclusion: Our data reveals a novel role for VISTA in reducing plaque development and in suppressing T cell activation, proliferation, and migration. Further characterization of T-cell specific VISTA-deficient mouse models and mechanistic insights into how VISTA modulates T cells are currently being investigated.

As a widely distributed network of cells, tissues, and organs, the human immune system is profoundly vulnerable to the effects of aging. Intrinsic and extrinsic stressors progressively erode its structural integrity and functional resilience, weakening core protective responses and increasing susceptibility to infection, malignancy, and tissue degeneration. At the same time, aging heightens the risk of chronic inflammation and autoimmune disease. Hematopoietic stem cells become uniquely compromised as aging intensifies metabolic and replicative stress. Their continuous high-volume turnover results in diminished self-renewal capacity, skewed lineage output, and dominance of expanded clones. These changes undermine innate immune competence and amplify inflammatory activity. Adaptive immune function declines with age through coordinated cellular and molecular programs. T and B lymphocytes exhibit a decline in naive cells, progressive loss of stemness, shortened lifespan, and constrained clonal diversity. Aging lymphocytes reconfigure transcriptional networks, undergo widespread organelle dysfunction, develop maladaptive stress responses, and redistribute into noncanonical tissue niches. Collectively, these alterations reduce antigen specificity and precision, promote innate-like immune behavior, and confer resistance to tolerance. These mechanisms result in concurrent immunodeficiency and autoimmunity, exemplified by two autoimmune diseases disproportionately affecting older adults: rheumatoid arthritis and giant cell arteritis.

Background Rheumatoid arthritis (RA) is an HLA-DR associated disease with a pivotal role of T cells in the pathogenesis. The mechanisms underlying the HLA association and the generation of a synovial T-cell response are unclear. We have hypothesized that the selection of the primary T-cell repertoire is a predisposing factor for rheumatoid synovitis. Methods The repertoire of T-cell receptors (TCR) expressed by circulating naive CD4 + CD45RO − T cells was compared in 10 patients with RA, 11 HLA-DR matched normal donors and 10 mismatched normal donors by determining the frequencies of TCR BV-BJ combinations in 3 different BV gene segment families. Clonally expanded synovium-specific CD4 T cells were identified in 8 patients by TCR BV-BJ-specific PCR of purified T-cell subsets followed by size fractionation and sequencing of the PCR product. The TCR BV-BJ repertoires of naive peripheral T cells and of synovial clones were compared. Results The repertoires of naive circulating CD4 + CD45RO − T cells were different in RA patients and in HLA-DR matched and unmatched controls, suggesting HLA-DR as well as disease-specific features of T-cell selection. To test the disease relevance of the shifts in the naive repertoire, CD4 T cells undergoing joint-specific clonal expansion were identified. The usage of BV-BJ gene combinations in these synovium-specific clones was biased and significantly different from the expected distribution with a preference for combinations favored in the naive TCR repertoire of RA patients. Conclusions These data suggest that primary T-cell selection in RA patients is of functional importance for the generation of synovium-specific T-cell responses. The synovial repertoire is influenced by aberrations in the naive T-cell repertoire that might indicate a defect in thymic education with the selection of high-affinity self-reactive T cells in RA.

Older adults are susceptible to infections in part due to waning of immune memory. To uncover mechanisms of a long-lasting immune memory, we contrasted varicella zoster virus antigen–specific memory T cell responses in adults vaccinated at young (<20 years) or older age (>50 years) with a live-attenuated vaccine conferring durable protection only when given at young age or with an adjuvanted component vaccine eliciting long-lasting immunity in older adults. Unlike VZV-specific CD4 + T cells, CD8 + T cells exhibited profound age-sensitive changes including memory subset shifts, reduced T cell receptor diversity, and loss of stem-like features. Vaccination of older adults with the adjuvanted vaccine did not restore CD8 + defects but selectively enhanced T helper 17 (T H 17) CD4 + T cells and prevented their conversion into regulatory T cells, likely through lipid metabolic regulation. Thus, durable vaccine efficacy with aging relies on antigen-specific T H 17 cells that compensate for CD8 + T cell defects.

Abstract Description The two key determinants of successful vaccines are the ability to induce a protective immune response and a long-lived immune memory. The mechanism determining durability and its contribution to the lower vaccine efficacy in older adults is elusive. We use varicella zoster virus (VZV) vaccination as a model that relies on cellular, not humoral immunity. We compared long-lived antigen-specific memory T cells in adults who were vaccinated at young (&lt;20 years) or older age (&gt;50 years) with a life-attenuated vaccine that confers sustained protection only in young age, or who received an adjuvanted subunit vaccine that is protective at older age. We stimulated PBMCs of vaccine recipients years after vaccination and collected VZV-reactive T cells for spectral flow cytometry and single-cell sequencing. While CD4 T cells were resilient to aging, VZV-specific CD8 T cells lost diversity and lacked stem-like features while gaining end-differentiated, NK-like signatures. These age-associated changes in CD8 T cells were not reversed with the effective subunit vaccine. Instead, this vaccine induced pro-inflammatory VZV-specific TH17 cells. TH17 cells in the less efficient vaccine response, albeit present, were skewed towards a FOXP3+ regulatory phenotype and deficient in TH1 polyfunctionality – a phenotypic shift that is in part controlled by lipid metabolic pathways. Our study uncovers traits of T cell dysfunction with age and informs vaccination efforts tailored towards healthy aging. Funding Sources NIH U19AI057266, R01AG045779, R01AI108891, R01AI129191, T32AG049672, Glenn Foundation for Medical Research Postdoctoral Fellowship, Robert and Arlene Kogod Center on Aging Career Development Award. Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)

Cardiovascular morbidity and mortality rise precipitously during the 6th–9th decades of life, identifying aging as a critical risk factor. Simultaneously, older individuals are susceptible to severe viral infection, raising the question whether shared mechanisms exist that predispose to both cardiovascular disease (CVD) and failing anti-viral immunity. The aging process causes steady decline in immune fitness (immune aging), which undermines the ability to generate protective anti-viral immune responses. Paradoxically, the aging immune system supports unopposed inflammatory pathways (inflammaging), which exacerbates tissue inflammation in CVD, specifically atherosclerosis. Here, we review the current evidence of how innate and adaptive immune aging promotes tissue-destructive inflammation in atherosclerosis while failing to fight viral infections. Further, we consider how these two disease processes mutually influence each other. We propose that mounting an effective anti-viral response induces off-target bystander activation and exhausts immune cells, ultimately exacerbating CVD. Additionally, we explore how atherosclerotic CVD impacts innate immunity through epigenetic modification of hematopoietic precursors and metabolically conditioning immune cells, leading to a dysfunctional immune system that accelerates plaque inflammation while simultaneously impairing host defense.

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.