Regulatory T Cells Sequentially Migrate from Inflamed Tissues to Draining Lymph Nodes to Suppress the Alloimmune Response

Overview

Journal Immunity

Publisher Cell Press

Specialty Allergy & Immunology

Date 2009 Mar 24

PMID 19303390

Citations 223

Authors

Nan Zhang

Bernd Schroppel

Girdhari Lal

Claudia Jakubzick

Xia Mao

Dan Chen

Na Yin

Rolf Jessberger

Jordi C Ochando

Yaozhong Ding

Jonathan S Bromberg

Affiliations

Soon will be listed here.

Abstract

To determine the site and mechanism of suppression by regulatory T (Treg) cells, we investigated their migration and function in an islet allograft model. Treg cells first migrated from blood to the inflamed allograft where they were essential for the suppression of alloimmunity. This process was dependent on the chemokine receptors CCR2, CCR4, and CCR5 and P- and E-selectin ligands. In the allograft, Treg cells were activated and subsequently migrated to the draining lymph nodes (dLNs) in a CCR2, CCR5, and CCR7 fashion; this movement was essential for optimal suppression. Treg cells inhibited dendritic cell migration in a TGF-beta and IL-10 dependent fashion and suppressed antigen-specific T effector cell migration, accumulation, and proliferation in dLNs and allografts. These results showed that sequential migration from blood to the target tissue and to dLNs is required for Treg cells to differentiate and execute fully their suppressive function.

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References

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

Hemmerich S, Butcher E, Rosen S . Sulfation-dependent recognition of high endothelial venules (HEV)-ligands by L-selectin and MECA 79, and adhesion-blocking monoclonal antibody. J Exp Med. 1994; 180(6):2219-26. PMC: 2191797. DOI: 10.1084/jem.180.6.2219. View

Palframan R, Jung S, Cheng G, Weninger W, Luo Y, Dorf M . Inflammatory chemokine transport and presentation in HEV: a remote control mechanism for monocyte recruitment to lymph nodes in inflamed tissues. J Exp Med. 2001; 194(9):1361-73. PMC: 2195988. DOI: 10.1084/jem.194.9.1361. View

Sarween N, Chodos A, Raykundalia C, Khan M, Abbas A, Walker L . CD4+CD25+ cells controlling a pathogenic CD4 response inhibit cytokine differentiation, CXCR-3 expression, and tissue invasion. J Immunol. 2004; 173(5):2942-51. DOI: 10.4049/jimmunol.173.5.2942. View

Schroppel B, Zhang N, Chen P, Zang W, Chen D, Hudkins K . Differential expression of chemokines and chemokine receptors in murine islet allografts: the role of CCR2 and CCR5 signaling pathways. J Am Soc Nephrol. 2004; 15(7):1853-61. DOI: 10.1097/01.asn.0000130622.48066.d9. View

Schroppel B, Zhang N, Chen P, Chen D, Bromberg J, Murphy B . Role of donor-derived monocyte chemoattractant protein-1 in murine islet transplantation. J Am Soc Nephrol. 2004; 16(2):444-51. DOI: 10.1681/ASN.2004090743. View

Grubin C, Kovats S, deRoos P, Rudensky A . Deficient positive selection of CD4 T cells in mice displaying altered repertoires of MHC class II-bound self-peptides. Immunity. 1997; 7(2):197-208. DOI: 10.1016/s1074-7613(00)80523-3. View

Zhang N, Richter A, Suriawinata J, Harbaran S, Altomonte J, Cong L . Elevated vascular endothelial growth factor production in islets improves islet graft vascularization. Diabetes. 2004; 53(4):963-70. DOI: 10.2337/diabetes.53.4.963. View

Mottet C, Uhlig H, Powrie F . Cutting edge: cure of colitis by CD4+CD25+ regulatory T cells. J Immunol. 2003; 170(8):3939-43. DOI: 10.4049/jimmunol.170.8.3939. View

10.

Shinohara M, Terada Y, Iwamatsu A, Shinohara A, Mochizuki N, Higuchi M . SWAP-70 is a guanine-nucleotide-exchange factor that mediates signalling of membrane ruffling. Nature. 2002; 416(6882):759-63. DOI: 10.1038/416759a. View

11.

Wagers A, Kansas G . Potent induction of alpha(1,3)-fucosyltransferase VII in activated CD4+ T cells by TGF-beta 1 through a p38 mitogen-activated protein kinase-dependent pathway. J Immunol. 2000; 165(9):5011-6. DOI: 10.4049/jimmunol.165.9.5011. View

12.

Tadokoro C, Shakhar G, Shen S, Ding Y, Lino A, Maraver A . Regulatory T cells inhibit stable contacts between CD4+ T cells and dendritic cells in vivo. J Exp Med. 2006; 203(3):505-11. PMC: 2118249. DOI: 10.1084/jem.20050783. View

13.

Fallarino F, Grohmann U, Hwang K, Orabona C, Vacca C, Bianchi R . Modulation of tryptophan catabolism by regulatory T cells. Nat Immunol. 2003; 4(12):1206-12. DOI: 10.1038/ni1003. View

14.

Sivalenka R, Jessberger R . SWAP-70 regulates c-kit-induced mast cell activation, cell-cell adhesion, and migration. Mol Cell Biol. 2004; 24(23):10277-88. PMC: 529030. DOI: 10.1128/MCB.24.23.10277-10288.2004. View

15.

Debes G, Arnold C, Young A, Krautwald S, Lipp M, Hay J . Chemokine receptor CCR7 required for T lymphocyte exit from peripheral tissues. Nat Immunol. 2005; 6(9):889-94. PMC: 2144916. DOI: 10.1038/ni1238. View

16.

Houot R, Perrot I, Garcia E, Durand I, Lebecque S . Human CD4+CD25high regulatory T cells modulate myeloid but not plasmacytoid dendritic cells activation. J Immunol. 2006; 176(9):5293-8. DOI: 10.4049/jimmunol.176.9.5293. View

17.

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

18.

Waldmann H, Adams E, Fairchild P, Cobbold S . Infectious tolerance and the long-term acceptance of transplanted tissue. Immunol Rev. 2006; 212:301-13. DOI: 10.1111/j.0105-2896.2006.00406.x. View

19.

Puccetti P, Grohmann U . IDO and regulatory T cells: a role for reverse signalling and non-canonical NF-kappaB activation. Nat Rev Immunol. 2007; 7(10):817-23. DOI: 10.1038/nri2163. View

20.

Forster R, Schubel A, Breitfeld D, Kremmer E, Renner-Muller I, Wolf E . CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell. 1999; 99(1):23-33. DOI: 10.1016/s0092-8674(00)80059-8. View