CXCR3+ Regulatory T Cells Control TH1 Responses in Crescentic GN

Hans-Joachim Paust, Jan-Hendrik Riedel, Christian F Krebs, Jan-Eric Turner, Silke R Brix, Sonja Krohn, Joachim Velden, Thorsten Wiech, Anna Kaffke, Anett Peters, Sabrina B Bennstein, Sonja Kapffer, Catherine Meyer-Schwesinger, Claudia Wegscheid, Gisa Tiegs, Friedrich Thaiss, Hans-Willi Mittrücker, Oliver M Steinmetz, Rolf A K Stahl, Ulf Panzer

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 (Foxp3(eGFP-Cre) × Cxcr3(fl/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-IFNγ 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.