Postdoctoral Fellow Asan Medical Center Seoul, Republic of Korea
Disclosure(s):
Eun-Ju Lee, PhD: No financial relationships to disclose
Introduction/Rationale: 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.
