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

Eur J Immunol. 2011 Aug;41(8):2291-302. doi: 10.1002/eji.201041095. Epub 2011 Jun 24.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cell Movement / immunology
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Chemokine CXCL10 / immunology
  • Chemokine CXCL10 / metabolism
  • Child
  • Flow Cytometry
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / immunology*
  • Forkhead Transcription Factors / metabolism
  • Gene Expression
  • Humans
  • Immunosuppressive Agents / pharmacology
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism
  • Kidney Transplantation
  • L-Selectin / genetics
  • L-Selectin / immunology
  • L-Selectin / metabolism
  • Lymphocyte Activation / immunology
  • Receptors, CCR4 / genetics
  • Receptors, CCR4 / immunology
  • Receptors, CCR4 / metabolism
  • Receptors, CXCR3 / genetics
  • Receptors, CXCR3 / immunology*
  • Receptors, CXCR3 / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sirolimus / pharmacology
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism


  • CCR4 protein, human
  • CXCR3 protein, human
  • Chemokine CXCL10
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Immunosuppressive Agents
  • Receptors, CCR4
  • Receptors, CXCR3
  • L-Selectin
  • Interferon-gamma
  • Sirolimus