# Exhaustion‐Resistant CD8 + T Cells in Ankylosing Spondylitis: A Proposed Three‐Axis Model

## TL;DR

The paper explores how certain CD8+ T cells in ankylosing spondylitis resist exhaustion and contribute to chronic inflammation and bone changes.

## Contribution

It introduces a novel three-axis model explaining the persistence of functional CD8+ T cells in ankylosing spondylitis.

## Key findings

- Exhaustion-resistant CD8+ T cells retain effector function and contribute to tissue inflammation and bone remodeling.
- A three-axis model involving TCR stimulation, IL-15/CD28 co-stimulation, and metabolic fitness explains CD8+ T cell persistence.
- Potential biomarkers and therapeutic strategies, such as JAK–IL-15 pathway modulation, are proposed.

## 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.

Exhaustion‐resistant CD8+ T cells may sustain ankylosing spondylitis. A three‐axis model—intermittent T‐cell receptor engagement, IL‐15/CD28 co‐stimulation and maintained metabolic fitness—explains how PD‐1^high CD8+ T cells retain effector function and accumulate from gut to entheses, promoting inflammation and aberrant bone remodelling. This concept yields measurable biomarkers (e.g., pSTAT5, TOX‐programme scores, metabolic flux) and therapeutic avenues, such as JAK–IL‐15 pathway modulation.