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. 2023 Apr:156:136-147.
doi: 10.1016/j.molimm.2023.03.008. Epub 2023 Mar 13.

Gal-9/Tim-3 signaling pathway activation suppresses the generation of Th17 cells and promotes the induction of Foxp3+ regulatory T cells in renal ischemia-reperfusion injury

Yamei Wang  1 , Ting Feng  2 , Hong Li  2 , Ying Xiong  3 , Yuhong Tao  4
Affiliations
Free article

Gal-9/Tim-3 signaling pathway activation suppresses the generation of Th17 cells and promotes the induction of Foxp3+ regulatory T cells in renal ischemia-reperfusion injury

Yamei Wang et al. Mol Immunol. 2023 Apr.
Free article

Abstract

CD4+ T cells mediate the pathogenesis of renal ischemia-reperfusion injury (IRI). Emerging research suggests that a Th17/regulatory T cell (Treg) imbalance plays a pivotal role in the development of renal IRI. A recently identified negative checkpoint protein, T cell immunoglobulin domain and mucin domain family 3 (Tim-3), inhibits the immune response by binding to its ligand, galectin-9 (Gal-9). However, the role of the Gal-9/Tim-3 signaling pathway in the regulation of CD4+ T cell subsets in renal IRI remains unclear. In this study, we investigated the effect of the Gal-9/Tim-3 signaling pathway on Th17/Treg subsets in renal IRI using a mouse model. Renal IRI induced the expression of Gal-9 in renal tubular epithelial cells and increased the proportion of Tim-3+ Th17 cells and Tim-3+ forkhead box P3 (Foxp3)+ Treg cells in the ischemia-reperfusion (IR) kidneys. Administration of rAAV9-Gal-9 suppressed kidney inflammation, reduced the mortality of mice with renal IRI, increased Foxp3+ Treg cells, and reduced Th17 cells. In contrast, the blockade of Tim-3 in vivo using an anti-Tim-3 monoclonal antibody aggravated renal inflammation, decreased Foxp3+ Treg cells, and promoted Th17 cells. Thus, Gal-9/Tim-3 signaling pathway activation may protect against renal IRI by inhibiting Th17 cell production and inducing Foxp3+ Treg cell expansion. Our study suggests that the Gal-9/Tim-3 signaling pathway may be targeted by immunotherapy in renal IRI.

Keywords: Galectin-9; Regulatory T cell; Renal ischemia-reperfusion injury; T cell immunoglobulin domain and mucin domain 3; Th17 cell.

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Conflict of interest statement

Conflict of interest The authors declare that they have no competing interests.

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