CXCR3+ regulatory T cells control TH1 responses in crescentic GN

Abstract

Chemokines and chemokine receptors are implicated in regulatory T cell (Treg) trafficking to sites of inflammation and suppression of excessive immune responses in inflammatory and autoimmune diseases; however, the specific requirements for Treg migration into the inflamed organs and the positioning of these cells within the tissue are incompletely understood. Here, we report that Tregs expressing the TH1–associated chemokine receptor CXCR3 are enriched in the kidneys of patients with ANCA–associated crescentic GN and colocalize with CXCR3+ effector T cells. To investigate the functional role of CXCR3+ Tregs, we generated mice that lack CXCR3 in Tregs specifically (Foxp3eGFP-Cre 3 Cxcr3fl/fl) and induced experimental crescentic GN. Treg-specific deletion of CXCR3 resulted in reduced Treg recruitment to the kidney and an overwhelming TH1 immune response, with an aggravated course of the nephritis that was reversible on anti-IFNg treatment. Together, these findings show that a subset of Tregs expresses CXCR3 and thereby, acquires trafficking properties of pathogenic CXCR3+ TH1 cells, allowing Treg localization and control of excessive TH1 responses at sites of inflammation.