Subsets of human CD4(+) regulatory T cells express the peripheral homing receptor CXCR3

Regulatory T cells (Tregs) migrate into peripheral sites of inflammation such as allografts undergoing rejection, where they serve to suppress the immune response. In this study, we find that ～30–40% of human CD25^hi FOXP3⁺ CD4⁺ Tregs express the peripheral CXC chemokine receptor 3 (CXCR3) and that this subset has potent immunoregulatory properties. Consistently, we observed that proliferative responses as well as IFN‐γ production were significantly higher using CXCR3‐depleted versus undepleted responders in the mixed lymphocyte reaction, as well as following mitogen‐dependent activation of T cells. Using microfluidics, we also found that CXCR3 was functional on CXCR3^pos Tregs, in as much as chemotaxis and directional persistence towards interferon‐γ‐inducible protein of 10 kDa (IP‐10) was significantly greater for CXCR3^pos than CXCR3^neg Tregs. Following activation, CXCR3‐expressing CD4⁺ Tregs were maintained in vitro in cell culture in the presence of the mammalian target of rapamycin (mTOR) inhibitor rapamycin, and we detected higher numbers of circulating CXCR3⁺ FOXP3⁺ T cells in adult and pediatric recipients of renal transplants who were treated with mTOR‐inhibitor immunosuppressive therapy. Collectively, these results demonstrate that the peripheral homing receptor CXCR3 is expressed on subset(s) of circulating human Tregs and suggest a role for CXCR3 in their recruitment into peripheral sites of inflammation.