Background: Among the various chemokines implicated in lupus nephritis (LN) pathogenesis, interferon-γ-inducible protein 10 (IP-10) is a major mediator that recruits immune cells and induces inflammation. Secreted IP-10 promotes the migration of CD8 ⁺ T cells and NK cells to the inflammatory site, inducing an inflammatory response in the kidneys and causing tissue damage. T stem-like cells have been shown to differentiate into terminally exhausted T-cells in chronic infection models when IP-10 levels increase or persist during chronic inflammation. However, it remains unclear whether CD8 ⁺ T-cells differentiate into the exhausted lineage and if IP-10 influences T-cell exhaustion in LN.

Objectives: This study aims to determine the role of IP-10 in the reduction of T stem-like cells and accumulation of terminally exhausted T-cells in LN.

Methods: Proteome profiler screening was performed on plasma samples obtained from patients with SLE (n=6), LN (n=6), and healthy controls (n=6). In MRL/lpr mice, serum was acquired bi-weekly from weeks 10 to 24, and the levels of serum anti-dsDNA, cytokines (BAFF, IL-16, CD30, Leptin, TIM-3, and VEGF), and chemokines (IP-10, MCP-1, MIG, and I-TAC) were measured using ELISA and Luminex assays. To evaluate CD8 ⁺ T cell differentiation in tissues, the spleen and kidney tissues was obtained and analyzed by flow cytometry at 10, 14, 18, and 24 weeks of age.

Results: Among the 105 circulating factors analyzed, IP-10 demonstrated the highest level of elevation in patients with SLE and LN compared to healthy controls. Correlation analysis of these factors revealed that in patients with LN, IP-10 was strongly associated with other immunoregulatory factors, such as MCP-1 and TIM-3. In the MRL/lpr mouse model, serum IP-10 levels increased with age and correlated with BAFF and anti-dsDNA levels. Additionally, flow cytometry analysis of spleen from MRL/lpr mice revealed that T stem-like cells (TCF1 ⁺ CX3CR1 ⁺ CD8 ⁺ ) within the tissue decreased and differentiated into an exhausted state, leading to the accumulation of terminally exhausted T-cells (TCF1 ^- CX3CR1 ^- CD8 ⁺ ) correlating with serum IP-10 levels. In the kidneys of MRL/lpr mice, terminally exhausted T-cells and IP-10 levels increased with age, showing a significant association over time (Figure 1).

Conclusions: The accumulation of terminally exhausted T-cells in the kidney was associated with the level of serum IP-10 in lupus prone mice, suggesting an interaction between IP-10 and the cells within the LN.

Figure 1.

Accumulation of terminally exhausted T cells in the kidney (A) and their correlation with serum IP-10 levels (B) in MRL/lpr LN mice. ****p < 0.0001, ***p < 0.001, **p < 0.01, *p < 0.05 vs. control (Mann-Whitney U test).

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Acknowledgments: NIL.

Disclosure of Interests: None declared.