Goronzy, Jorg

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.

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.

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.

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.

ABSTRACTImmunotherapy of autoimmune diseases has expanded substantially, yet autoimmunity remains incurable, and patients suffer from chronic destructive tissue inflammation that fails to resolve. Mechanisms underlying the endurance of autoimmune memory and the lack of exhaustion are beginning to be understood. Here, we review emerging data on how decentralization of cellular immunity contributes to persistent autoimmune responses and chronicity of autoimmune tissue inflammation. Two processes are recognized as ensuring lasting immune memory: the generation of tissue‐resident memory T cells (TRM) and the formation of tertiary lymphoid structures (TLS). TLS, lymphoid aggregates formed outside of lymphoid organs, develop under conditions of chronic immune stimulation, such as autoimmune disease, anti‐tumor immunity, and during immune aging. TLS display heterogeneity in structure and cellular composition that may determine whether they ultimately serve as protective or pathogenic elements. Recent data have implicated TLS as a critical resource in upholding autoimmune responses, emphasizing their role in harming the host. In patients with autoimmune vasculitis, adventitial TLS drives protracted autoimmune disease by housing TCF1hi CD4+ T stem cells that escape exhaustion and provide a continuous supply of pathogenic effector T cells to the disease lesions. The local production and stemness of CD4+ T cells bring resilience to autoreactive immunity, defining novel therapeutic targets in the management of autoimmune disease.

ABSTRACT Older adults are susceptible to infections, in part due to waning of immune memory. To determine mechanisms that determine long-lasting versus short-term immunity, we examined varicella zoster virus (VZV) vaccination as a model system. We contrasted VZV antigen-specific T cells several years after vaccination in adults who had been vaccinated at young (<20 years) or older age (>50 years) with a live-attenuated vaccine that confers durable protection only when given at young age, or with an adjuvanted VZV component vaccine that elicits effective, long-lasting immunity in older adults. CD8 + T cells were highly sensitive to age-related changes showing T cell subset shifts, loss in TCR diversity and reduced stem-like features while gaining NK-like signatures without evidence for cellular senescence or exhaustion. VZV-specific CD4 + T cells were largely resilient to age and maintained phenotypic and TCR diversity. Immunization of older adults with the adjuvanted VZV vaccine did not reverse age-associated defects in CD8 + T cells. Instead, it selectively improved the functionality of VZV-specific Th17 CD4 + T cells and prevented their acquisition of Treg features, likely as consequence of lipid metabolic pathways. Collectively, our data indicate that effective vaccination in older adults is supported by the generation of a durable, antigen-specific CD4 + Th17 population that resists mis-differentiation into Tregs and that compensates for age-related defects in CD8 + T cells. One sentence summary Aging primarily impairs the CD8 + T cell VZV vaccine response, while effective VZV vaccination in older adults induces antigen-specific Th17 CD4 + T cells to compensate for aging defects.

T cell aging contributes to the lower vaccine efficacy in older adults, yet the molecular mechanism remains elusive. Here, we show the density of initially responding naïve CD4 + T cells is instructive in T follicular helper (TFH) cell fate decisions and declines with age. A lower number of initially responding cells did not affect TFH differentiation at peak responses after immunization but accounted for an increased contraction phase manifesting as a larger loss of CXCR5 expression. Mechanistically, cells activated at a lower initial density had more sustained mammalian target of rapamycin complex 1 (mTORC1) activities that impair CXCR5 maintenance. YAP-dependent regulation of SLC7A5 involved in the cell density–dependent regulation of mTORC1 activities and TFH loss. Old mice fed with a leucine-restricted diet after peak responses showed smaller TFH loss and improved humoral immune responses. Attenuating mTORC1 signaling after peak response is a strategy to boost vaccine responses in older individuals.

Rheumatoid arthritis (RA) is a life‐long autoimmune disease caused by the confluence of genetic and environmental variables that lead to loss of self‐tolerance and persistent joint inflammation. RA occurs at the highest incidence in individuals >65 years old, implicating the aging process in disease susceptibility. Transformative approaches in molecular immunology and in functional genomics have paved the way for pathway paradigms underlying the replacement of immune homeostasis with autodestructive immunity in affected patients, including the process of immune aging. Patients with RA have a signature of premature immune aging, best understood for CD4 + T cells, which function as pathogenic effectors in this HLA class II–associated disease. Premature immune aging is present in healthy HLA–DRB1*04 + individuals, placing accelerated immune aging before joint inflammation. Aging‐related molecular abnormalities directly implicated in turning RA CD4 + T cells into proinflammatory effector cells are linked to malfunction of subcellular organelles, such as mitochondria, lysosomes, lipid droplets, and the endoplasmic reticulum. Resulting changes in T cell behavior include cellular hypermobility, tissue invasiveness, unopposed mammalian target of rapamycin complex (mTORC)1 activation, excessive release of tumor necrosis factor, lysosomal failure, clonal expansion, and immunogenic cell death. Aged and metabolically reprogrammed T cells in patients with RA are accompanied by age‐associated B cells, which specialize in autoantibody production. Clonal hematopoiesis drives myeloid cell aging by producing aged monocytes and hypermetabolic macrophages, which sustain the process of inflammaging. Here, we synthesize insights into the relationship of RA risk and immune aging and discuss mechanisms through which immune aging can cause autoimmunity. image

The human adult immune system maintains normal T cell counts and compensates for T cell loss throughout life, mainly through peripheral homeostatic proliferation after the ability of the thymus to generate new T cells has rapidly declined at adolescence. This process is mainly driven by STAT5-activating cytokines, most importantly IL-7, and is very effective in maintaining a large naive CD4 + T cell compartment into older age. Here, we describe that naive CD4 + T cells undergo adaptations to optimize IL-7 responses by upregulating the guanine-nucleotide exchange factor PREX1 in older age. PREX1 promotes nuclear translocation of phosphorylated STAT5, thereby supporting homeostatic proliferation in response to IL-7. Through the same mechanism, increased expression of PREX1 also biases naive cells to differentiate into effector T cells. These findings are consistent with the concept that primarily beneficial adaptations during aging, i.e., improved homeostasis, account for unfavorable functions of the aged immune system, in this case biased differentiation.

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.