How Exhausted and Aged Immune Cells May Drive Chronic Pain

Chronic pain, defined as pain lasting more than three months, is among the most disabling conditions worldwide, yet it still lacks objective biomarkers and mechanistic clarity. Three of the top four global causes of disability—back pain, musculoskeletal disorders, and neck pain—fall under this umbrella, underscoring the urgency of better biological understanding.

This narrative review from the Pain in Motion Research Group (VUB, Brussels) and collaborating institutions synthesizes evidence linking two specific immune dysfunction states—T cell exhaustion and T cell senescence—to chronic pain pathophysiology. T cell exhaustion, driven by persistent antigenic overstimulation (as in cancer or chronic viral infection), is characterized by upregulation of inhibitory receptors (PD-1, CTLA-4, Tim-3, LAG-3, TIGIT), impaired cytokine production (IL-2, IFN-γ, TNF-α), and transcriptional dysregulation of T-bet, Eomes, and TCF-1. Crucially, exhaustion is potentially reversible via immune checkpoint inhibitors. T cell senescence, in contrast, represents irreversible cell-cycle arrest marked by telomere shortening, loss of CD27/CD28, gain of KLRG-1 and CD57, and a pro-inflammatory senescence-associated secretory phenotype (SASP) releasing IL-6, IL-10, TNF-α, and IFN-γ—cytokines directly implicated in neuroinflammation and central sensitization relevant to chronic pain.

The review systematically examines how four lifestyle domains modulate these immune states. Sleep fragmentation correlates with expansion of late-differentiated CD8+CD28− senescent-like T cells, while not significantly altering PD-1 (an exhaustion marker), suggesting sleep disruption may preferentially promote senescence. Chronic psychological stress activates the HPA axis, elevating glucocorticoids that can both suppress and reshape T cell populations, with chronic stress nudging cells toward exhaustion-like phenotypes. Physical activity has a dual profile: acute vigorous exercise transiently mobilizes PD-1-high T cells, but regular moderate exercise is associated with reduced markers of senescence, improved telomere length, and lower SASP signaling. Diet—particularly Mediterranean and anti-inflammatory dietary patterns—is linked to reduced systemic inflammation and lower senescent cell burden, while high-fat and ultra-processed diets promote oxidative stress that can accelerate both exhaustion and senescence.

The authors highlight a striking and clinically important knowledge gap: despite extensive characterization of T cell exhaustion and senescence in oncology and infectious disease (where they enabled checkpoint inhibitor therapies), almost no studies have directly assessed these phenotypes in chronic pain populations. Existing chronic pain immunology research is largely limited to non-specific cytokine profiling and small sample sizes, leaving the mechanistic contribution of exhausted or senescent T cells entirely uncharacterized.

The review proposes that lifestyle-driven immune dysfunction—particularly senescence-associated neuroinflammation—may represent a tractable biological pathway connecting modifiable behaviors to chronic pain persistence. Future research should combine deep T cell phenotyping (multi-parameter flow cytometry, transcriptomics) with longitudinal lifestyle assessment in well-characterized chronic pain cohorts. Senolytic drugs and immune checkpoint modulation are flagged as potential therapeutic avenues warranting investigation in this context.