Potential Defensive Role of TIM-3 on T Lymphocytes in the Inflammatory Involvement of Diabetic Kidney Disease

Background: The aberrant mobilization and activation of various T lymphocyte subpopulations play a pivotal role in the pathogenesis of diabetic kidney disease (DKD), yet the regulatory mechanisms underlying these processes remain poorly understood. The dysregulation of immune checkpoint molecules on T lymphocytes disrupts kidney homeostasis, instigates pathological inflammation, and promotes DKD progression ,becoming a new derection for detecting the mechanism of DKD. Methods: A total of 360 adult patients with DKD were recruited for this study. The expression of immune checkpoint molecules on T lymphocytes was assessed by flow cytometry for peripheral blood and immunofluorescence staining for kidney tissue. Single-cell sequencing (scRNA-seq) data from the kidneys of DKD mouse model were analyzed. Results: Patients with DKD exhibited a reduction in the proportion of CD3+TIM-3+ T cells in circulation concurrent with the emergence of significant albuminuria and hematuria (p=0.008 and 0.02, respectively). Conversely, the incidence of infection during DKD progression correlated with an elevation of peripheral CD3+TIM-3+ T cells (p=0.01). Both univariate and multivariate logistic regression analysis revealed a significant inverse relationship between the proportion of peripheral CD3+TIM-3+ T cells and severe interstitial mononuclear infiltration (OR: 0.193, 95%CI: 0.040,0.926, p=0.04). Immunofluorescence assays demonstrated an increase of CD3+, TIM-3+ and CD3+TIM 3+ interstitial mononuclear cells in the kidneys of DKD patients as compared to patients diagnosed of minimal change disease (p=0.03, 0.02 and 0.002, respectively). seq analysis revealed decreased gene expression of TIM3 on T lymphocytes in DKD compared to control. And TIM3's main ligands, Galectin-9 on immune cells showed a decreasing trend in gene expression as kidney damage worsened. Conclusion: Our study underscores the potential protective role of TIM-3 on T lymphocytes in attenuating the progression of DKD and suggests that monitoring circulating CD3+TIM3+ T cells may serve as a viable strategy for identifying DKD patients at heightened risk of disease progression. Funding: Government Support – Non-U.S.