CXCR3+ Regulatory T Cells Control TH1 Responses in Crescentic GN

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 T(H)1-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 (Foxp3(eGFP-Cre) x Cxcr3(fl/fl)) and induced experimental crescentic GN. Treg-specific deletion of CXCR3 resulted in reduced Treg recruitment to the kidney and an overwhelming T(H)1 immune response, with an aggravated course of the nephritis that was reversible on anti-IFN gamma treatment. Together, these findings show that a subset of Tregs expresses CXCR3 and thereby, acquires trafficking properties of pathogenic CXCR3(+) T(H)1 cells, allowing Treg localization and control of excessive T(H)1 responses at sites of inflammation.