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

Abstract

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.

• Authors: André Hoerning, Kerith Koss, Dipak Datta, Leonard Boneschansker, Caroline N Jones, Ian Y Wong, Daniel Irimia, Katiana Calzadilla, Fanny Benitez, Peter F Hoyer, William E Harmon, David M Briscoe
• Journal: European journal of immunology (Eur J Immunol) Vol. 41 Issue 8 Pg. 2291-302 (Aug 2011) ISSN: 1521-4141 [Electronic] Germany
• PMID: 21538345 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• 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

Topics

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