Exhaustion-Resistant CD8+ T Cells in Ankylosing Spondylitis: A Proposed Three-Axis Model.

Abstract

Ankylosing spondylitis (AS) is a chronic immune-mediated disease marked by sustained joint inflammation and aberrant bone remodelling. Although chronic antigen exposure usually enforces terminal exhaustion, emerging evidence indicates that a subset of CD8⁺ T cells in AS evades canonical exhaustion programmes while expressing programmed cell death protein 1 (PD-1). These exhaustion-resistant cells retain effector function and likely contribute to persistent tissue inflammation and structural damage. In this review, we dissect the cellular and molecular basis of exhaustion resistance in AS CD8⁺ T cells and focus on the convergence of intermittent T cell receptor (TCR) stimulation, metabolic adaptation that preserves mitochondrial fitness, and co-stimulatory inputs from interleukin-15 (IL-15) and CD28. We propose an integrated three-axis model governing CD8⁺ T cell fate and functional persistence in the AS context shaped by human leukocyte antigen-B27 (HLA-B27) and the gut-joint axis. Clarifying these mechanisms refines current views of T cell dysfunction in chronic inflammation and highlights therapeutic strategies aimed at reprogramming pathogenic immunity in AS.