Differentiation and Pathological Significance of Tissue‐Resident Memory‐Like CD8 + T Cells in Systemic Lupus Erythematosus

Objective Tissue‐resident memory T (T RM ) cells have been implicated in organ‐specific immune pathology; however, the pathological relevance of T RM ‐like CD8 + T cells in systemic lupus erythematosus (SLE) remains unclear. We investigated their differentiation mechanisms and pathological significance in SLE, including associations with disease activity and organ involvement. Methods Peripheral blood samples from 30 treatment‐naïve patients with SLE, 40 patients with rheumatoid arthritis (RA), and 30 healthy donors (HDs) were analyzed by flow cytometry. Renal biopsy specimens from 20 patients with SLE were examined by immunofluorescence. Naïve CD8 + T cells from HDs were stimulated with cytokines to induce T RM ‐like differentiation, followed by phenotypic, functional, transcriptional, and metabolic analyses. The effects of Janus kinase (JAK) inhibitors were assessed. Results Circulating CD8 + CD69 + CD103 + T RM ‐like cells were more frequent in SLE than in RA and HDs ( P=0.022 and P<0.001 , respectively) and correlated with anti‐dsDNA antibodies (rs=0.468, P=0.016 ) and CH50 (rs=−0.397, P=0.045 ). Patients with active kidney involvement (renal BILAG A/B; n=17) had higher T RM ‐like cell proportions than those without active kidney involvement (n=13; P<0.05 ). CD3 + CD103 + cells in renal lesions expressed granzyme B or interferon‐γ. Patients with baseline T RM ‐like cell proportions ≥0.40% had higher urine protein‐to‐creatinine ratios and SELENA‐SLEDAI scores at week 24 (both P<0.05 ). IL‐15 plus TGF‐β1 induced T RM ‐like differentiation with effector, transcriptional, survival, and metabolic features, whereas JAK inhibition suppressed differentiation and granzyme B expression. Conclusion Circulating T RM ‐like CD8 + T cells were associated with SLE activity and kidney involvement. IL‐15/TGF‐β1‐dependent differentiation partly involved JAK/STAT signaling, supporting further evaluation as a biomarker and therapeutic target. image