IP-10 Drives TCF1+ Stem-like CD8+ T Cell Depletion and Terminal Differentiation in Lupus Nephritis 2308427

Abstract

Abstract Introduction Lupus nephritis (LN) is characterized by kidney damage due to immune dysregulation. CD8+ T cell dysfunction contributes to tissue injury, however, the mechanisms regulating CD8+ T cell fate during autoimmunity remain unclear. In particular, the effect of inflammatory chemokines on the balance between stem-like and terminally differentiated CD8+ T cells in the LN is poorly understood. Here, we investigated whether IP-10 acts as a key regulator of CD8+ T cell differentiation and tissue redistribution in the LN. Methods Plasma levels of 105 immune-related proteins were profiled in HC, patients with SLE, and patients with LN. Using longitudinal analyses of MRL/lpr lupus mice, we performed multiplex profiling of circulating inflammatory mediators together with immunophenotypic analysis of splenic and renal CD8+ T cell subtypes, including TCF1+ stem-like, effector, terminally differentiated and PD-1+ cells. Correlation analyses linked IP-10 levels with immune mediators and CD8+ T cell subtypes, and functional relevance was assessed using anti-IP-10 antibody treatment in MRL/lpr mice. Results Among the 105 circulating factors analyzed, IP-10 showed the highest elevation. and showed strong correlations with immune checkpoint molecules, particularly with TIM-3. In MRL/lpr mice, IP-10 was markedly elevated during disease progression and showed strong correlations with BAFF, IL-15, TIM-3, and PDL2. Increased IP-10 levels were also associated with a progressive loss of TCF1+ stem-like CD8+ T cells and a concomitant enrichment of terminally differentiated and PD-1+ CD8 T cells within the kidney. Blockade of IP-10 restored the attenuated pathogenic immune activation. Conclusion Our data reveal IP-10 as a key regulator of CD8+ T-cell fate in the LN. By promoting stem-like CD8+ T-cell depletion and terminal differentiation, IP-10 contributes to the sustained renal immune injury. Modulation of the IP-10—CXCR3 pathway may offer new opportunities to reprogram pathogenic T cell responses in chronic autoimmunity. Funding Source This work was supported by the National Research Foundation of Korea (RS-2024-00348380, RS-2022-NR069963). Topic Categories Basic Autoimmunity (BA)