Critical Role for CCR5 in the Function of Donor CD4+CD25+ Regulatory T Cells During Acute Graft-versus-host Disease

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2005 Jul 9

PMID 16002422

Citations 104

Authors

Christian A Wysocki

Qi Jiang

Angela Panoskaltsis-Mortari

Patricia A Taylor

Karen P McKinnon

Lishan Su

Bruce R Blazar

Jonathan S Serody

Affiliations

Soon will be listed here.

Abstract

CD4+CD25+ regulatory T cells (T(regs)) have been shown to inhibit graft-versus-host disease (GVHD) in murine models, and this suppression was mediated by T(regs) expressing the lymphoid homing molecule l-selectin. Here, we demonstrate that T(regs) lacking expression of the chemokine receptor CCR5 were far less effective in preventing lethality from GVHD. Survival of irradiated recipient animals given transplants supplemented with CCR5-/- T(regs) was significantly decreased, and GVHD scores were enhanced compared with animals receiving wild-type (WT) T(regs). CCR5-/- T(regs) were functional in suppressing T-cell proliferation in vitro and ex vivo. However, although the accumulation of T(regs) within lymphoid tissues during the first week after transplantation was not dependent on CCR5, the lack of function of CCR5-/- T(regs) correlated with impaired accumulation of these cells in the liver, lung, spleen, and mesenteric lymph node, more than one week after transplantation. These data are the first to definitively demonstrate a requirement for CCR5 in T(reg) function, and indicate that in addition to their previously defined role in inhibiting effector T-cell expansion in lymphoid tissues during GVHD, later recruitment of T(regs) to both lymphoid tissues and GVHD target organs is important in their ability to prolong survival after allogeneic bone marrow transplantation.

Citing Articles

Control of antigen-independent T-cell migration after HSCT.

Koyama M Blood Adv. 2025; 9(1):207-208.

PMID: 39808447 PMC: 11788125. DOI: 10.1182/bloodadvances.2024014584.

Dendritic Cells Pulsed with HAM/TSP Exosomes Sensitize CD4 T Cells to Enhance HTLV-1 Infection, Induce Helper T-Cell Polarization, and Decrease Cytotoxic T-Cell Response.

Joseph J, Premeaux T, Tandon R, Murphy E, Bruhn R, Nicot C Viruses. 2024; 16(9).

PMID: 39339919 PMC: 11436225. DOI: 10.3390/v16091443.

Chemokine receptors are required for effector T-cell trafficking to GVHD tissues but not to bone marrow.

Zhao K, Zhu J, Rosenberger S, Rosenberger S, Zhou M, Shlomchik W Blood Adv. 2024; 9(1):209-221.

PMID: 39172160 PMC: 11788131. DOI: 10.1182/bloodadvances.2024013291.

Human gut microbiota-reactive DP8α Tregs prevent acute graft-versus-host disease in a CD73-dependent manner.

Godefroy E, Chevallier P, Haspot F, Vignes C, Daguin V, Lambot S JCI Insight. 2024; 9(18).

PMID: 39088302 PMC: 11457850. DOI: 10.1172/jci.insight.179458.

The role of regulatory T cells in vitiligo and therapeutic advances: a mini-review.

Jin S, Wan S, Xiong R, Li Y, Dong T, Guan C Inflamm Res. 2024; 73(8):1311-1332.

PMID: 38839628 DOI: 10.1007/s00011-024-01900-w.

References

Fisson S, Darrasse-Jeze G, Litvinova E, Septier F, Klatzmann D, Liblau R . Continuous activation of autoreactive CD4+ CD25+ regulatory T cells in the steady state. J Exp Med. 2003; 198(5):737-46. PMC: 2194185. DOI: 10.1084/jem.20030686. View

Green E, Gorelik L, McGregor C, Tran E, Flavell R . CD4+CD25+ T regulatory cells control anti-islet CD8+ T cells through TGF-beta-TGF-beta receptor interactions in type 1 diabetes. Proc Natl Acad Sci U S A. 2003; 100(19):10878-83. PMC: 196896. DOI: 10.1073/pnas.1834400100. View

Trenado A, Charlotte F, Fisson S, Yagello M, Klatzmann D, Salomon B . Recipient-type specific CD4+CD25+ regulatory T cells favor immune reconstitution and control graft-versus-host disease while maintaining graft-versus-leukemia. J Clin Invest. 2003; 112(11):1688-96. PMC: 281639. DOI: 10.1172/JCI17702. View

Reddy P . Pathophysiology of acute graft-versus-host disease. Hematol Oncol. 2004; 21(4):149-61. DOI: 10.1002/hon.716. View

Wysocki C, Burkett S, Panoskaltsis-Mortari A, Kirby S, Luster A, McKinnon K . Differential roles for CCR5 expression on donor T cells during graft-versus-host disease based on pretransplant conditioning. J Immunol. 2004; 173(2):845-54. DOI: 10.4049/jimmunol.173.2.845. View

Hanash A, Levy R . Donor CD4+CD25+ T cells promote engraftment and tolerance following MHC-mismatched hematopoietic cell transplantation. Blood. 2004; 105(4):1828-36. DOI: 10.1182/blood-2004-08-3213. View

Ermann J, Hoffmann P, Edinger M, Dutt S, Blankenberg F, Higgins J . Only the CD62L+ subpopulation of CD4+CD25+ regulatory T cells protects from lethal acute GVHD. Blood. 2004; 105(5):2220-6. DOI: 10.1182/blood-2004-05-2044. View

Fontenot J, Rasmussen J, Williams L, Dooley J, Farr A, Rudensky A . Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity. 2005; 22(3):329-41. DOI: 10.1016/j.immuni.2005.01.016. View

Lee I, Wang L, Wells A, Dorf M, Ozkaynak E, Hancock W . Recruitment of Foxp3+ T regulatory cells mediating allograft tolerance depends on the CCR4 chemokine receptor. J Exp Med. 2005; 201(7):1037-44. PMC: 2213137. DOI: 10.1084/jem.20041709. View

10.

Wan Y, Flavell R . Identifying Foxp3-expressing suppressor T cells with a bicistronic reporter. Proc Natl Acad Sci U S A. 2005; 102(14):5126-31. PMC: 556008. DOI: 10.1073/pnas.0501701102. View

11.

Sato N, Kuziel W, Melby P, Reddick R, Kostecki V, Zhao W . Defects in the generation of IFN-gamma are overcome to control infection with Leishmania donovani in CC chemokine receptor (CCR) 5-, macrophage inflammatory protein-1 alpha-, or CCR2-deficient mice. J Immunol. 1999; 163(10):5519-25. View

12.

van den Brink M, Moore E, Horndasch K, Crawford J, Hoffman J, Murphy G . Fas-deficient lpr mice are more susceptible to graft-versus-host disease. J Immunol. 1999; 164(1):469-80. DOI: 10.4049/jimmunol.164.1.469. View

13.

Murphy P, Baggiolini M, Charo I, Hebert C, Horuk R, Matsushima K . International union of pharmacology. XXII. Nomenclature for chemokine receptors. Pharmacol Rev. 2000; 52(1):145-76. View

14.

Salomon B, Lenschow D, Rhee L, Ashourian N, Singh B, Sharpe A . B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity. 2000; 12(4):431-40. DOI: 10.1016/s1074-7613(00)80195-8. View

15.

Dawson T, Beck M, Kuziel W, Henderson F, Maeda N . Contrasting effects of CCR5 and CCR2 deficiency in the pulmonary inflammatory response to influenza A virus. Am J Pathol. 2000; 156(6):1951-9. PMC: 1850091. DOI: 10.1016/S0002-9440(10)65068-7. View

16.

Panoskaltsis-Mortari A, Strieter R, Hermanson J, Fegeding K, Murphy W, Farrell C . Induction of monocyte- and T-cell-attracting chemokines in the lung during the generation of idiopathic pneumonia syndrome following allogeneic murine bone marrow transplantation. Blood. 2000; 96(3):834-9. View

17.

Petrek M, Drabek J, Kolek V, Zlamal J, Welsh K, Bunce M . CC chemokine receptor gene polymorphisms in Czech patients with pulmonary sarcoidosis. Am J Respir Crit Care Med. 2000; 162(3 Pt 1):1000-3. DOI: 10.1164/ajrccm.162.3.2001022. View

18.

Serody J, Burkett S, Panoskaltsis-Mortari A, McMahon E, Matsushima G, Lira S . T-lymphocyte production of macrophage inflammatory protein-1alpha is critical to the recruitment of CD8(+) T cells to the liver, lung, and spleen during graft-versus-host disease. Blood. 2000; 96(9):2973-80. View

19.

Hara M, Kingsley C, Niimi M, Read S, Turvey S, Bushell A . IL-10 is required for regulatory T cells to mediate tolerance to alloantigens in vivo. J Immunol. 2001; 166(6):3789-96. DOI: 10.4049/jimmunol.166.6.3789. View

20.

Woo E, Chu C, Goletz T, Schlienger K, Yeh H, Coukos G . Regulatory CD4(+)CD25(+) T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. Cancer Res. 2001; 61(12):4766-72. View