title: 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.affiliation: Department of Medicine, Children's Hospital Boston, Boston, MA, USA.
authors.forename: André
authors.initials: A
authors.lastname: Hoerning
authors.forename: Kerith
authors.initials: K
authors.lastname: Koss
authors.forename: Dipak
authors.initials: D
authors.lastname: Datta
authors.forename: Leonard
authors.initials: L
authors.lastname: Boneschansker
authors.forename: Caroline N
authors.initials: CN
authors.lastname: Jones
authors.forename: Ian Y
authors.initials: IY
authors.lastname: Wong
authors.forename: Daniel
authors.initials: D
authors.lastname: Irimia
authors.forename: Katiana
authors.initials: K
authors.lastname: Calzadilla
authors.forename: Fanny
authors.initials: F
authors.lastname: Benitez
authors.forename: Peter F
authors.initials: PF
authors.lastname: Hoyer
authors.forename: William E
authors.initials: WE
authors.lastname: Harmon
authors.forename: David M
authors.initials: DM
authors.lastname: Briscoe
mesh_terms: D000328:Adult; D002465:Cell Movement / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000276:immunology / Q000378:metabolism; D002648:Child; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D016030:Kidney Transplantation; D019041:L-Selectin / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D054398:Receptors, CCR4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020123:Sirolimus / Q000494:pharmacology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
chemical_list: C515354:CCR4 protein, human; C515187:CXCR3 protein, human; D054357:Chemokine CXCL10; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007166:Immunosuppressive Agents; D054398:Receptors, CCR4; D054367:Receptors, CXCR3; D019041:L-Selectin; D007371:Interferon-gamma; D020123:Sirolimus