GM-CSF-induced CD11c+CD8a--dendritic Cells Facilitate Foxp3+ and IL-10+ Regulatory T Cell Expansion Resulting in Suppression of Autoimmune Thyroiditis

Overview

Journal Int Immunol

Specialty Allergy & Immunology

Date 2009 Jan 29

PMID 19174473

Citations 58

Authors

Balaji B Ganesh

Donald M Cheatem

Jian Rong Sheng

Chenthamarakshan Vasu

Bellur S Prabhakar

Affiliations

Soon will be listed here.

Abstract

GM-CSF plays an essential role in the differentiation of dendritic cells (DCs). Our studies have shown that GM-CSF treatment can induce semi-mature DCs and CD4+CD25+ regulatory T cells (Tregs) and suppress ongoing autoimmunity in mouse models. In this study, we examined the differences in the potential of GM-CSF to exert tolerogenic function on CD8a+ and CD8a- sub-populations of DCs in vivo. We show that GM-CSF modulates CD8a-, but not CD8a+ DCs in vivo, by inhibiting the surface expression of activation markers MHC II and CD80 and production of inflammatory cytokines such as IL-12 and IL-1beta. Self-antigen [mouse thyroglobulin (mTg)] presentation by GM-CSF-exposed CD8a- DCs to T cells from mTg-primed mice induced a profound increase in the frequency of forkhead box P3 (FoxP3)-expressing T cells compared with antigen presentation by GM-CSF-exposed CD8a+ DCs and control CD8a+ and CD8a- DCs. This tolerogenic property of GM-CD8a- DCs was abrogated when IL-12 was added. GM-CSF-exposed CD8a- DCs could also induce secretion of significantly higher amounts of IL-10 by T cells from mTg-primed mice. Importantly, adoptive transfer of CD8a- DCs from GM-CSF-treated SCID mice, but not untreated mice, into wild-type CBA/J mice prevented the development of experimental autoimmune thyroiditis (EAT) in the recipient animals upon immunization with mTg. Collectively, our results show that GM-CSF renders CD8a- DCs tolerogenic, and these DCs induce Foxp3+ and IL-10+ Tregs.

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References

Takahashi T, KUNIYASU Y, Toda M, Sakaguchi N, Itoh M, Iwata M . Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state. Int Immunol. 1999; 10(12):1969-80. DOI: 10.1093/intimm/10.12.1969. View

Apostolou I, Sarukhan A, Klein L, von Boehmer H . Origin of regulatory T cells with known specificity for antigen. Nat Immunol. 2002; 3(8):756-63. DOI: 10.1038/ni816. View

Gavin M, Clarke S, Negrou E, Gallegos A, Rudensky A . Homeostasis and anergy of CD4(+)CD25(+) suppressor T cells in vivo. Nat Immunol. 2001; 3(1):33-41. DOI: 10.1038/ni743. View

Morris G, Chen L, Kong Y . CD137 signaling interferes with activation and function of CD4+CD25+ regulatory T cells in induced tolerance to experimental autoimmune thyroiditis. Cell Immunol. 2004; 226(1):20-9. DOI: 10.1016/j.cellimm.2003.11.002. View

Dogan R, Vasu C, Holterman M, Prabhakar B . Absence of IL-4, and not suppression of the Th2 response, prevents development of experimental autoimmune Graves' disease. J Immunol. 2003; 170(4):2195-204. DOI: 10.4049/jimmunol.170.4.2195. View

Bonifaz L, Bonnyay D, Mahnke K, Rivera M, Nussenzweig M, Steinman R . Efficient targeting of protein antigen to the dendritic cell receptor DEC-205 in the steady state leads to antigen presentation on major histocompatibility complex class I products and peripheral CD8+ T cell tolerance. J Exp Med. 2002; 196(12):1627-38. PMC: 2196060. DOI: 10.1084/jem.20021598. View

Kared H, Masson A, Adle-Biassette H, Bach J, Chatenoud L, Zavala F . Treatment with granulocyte colony-stimulating factor prevents diabetes in NOD mice by recruiting plasmacytoid dendritic cells and functional CD4(+)CD25(+) regulatory T-cells. Diabetes. 2004; 54(1):78-84. DOI: 10.2337/diabetes.54.1.78. View

Lau A, Biester S, Cornall R, Forrester J . Lipopolysaccharide-activated IL-10-secreting dendritic cells suppress experimental autoimmune uveoretinitis by MHCII-dependent activation of CD62L-expressing regulatory T cells. J Immunol. 2008; 180(6):3889-99. DOI: 10.4049/jimmunol.180.6.3889. View

Morris G, Yan Y, David C, Kong Y . H2A- and H2E-derived CD4+CD25+ regulatory T cells: a potential role in reciprocal inhibition by class II genes in autoimmune thyroiditis. J Immunol. 2005; 174(5):3111-6. DOI: 10.4049/jimmunol.174.5.3111. View

10.

Morris G, Kong Y . Interference with CD4+CD25+ T-cell-mediated tolerance to experimental autoimmune thyroiditis by glucocorticoid-induced tumor necrosis factor receptor monoclonal antibody. J Autoimmun. 2005; 26(1):24-31. DOI: 10.1016/j.jaut.2005.09.003. View

11.

Kretschmer K, Apostolou I, Hawiger D, Khazaie K, Nussenzweig M, von Boehmer H . Inducing and expanding regulatory T cell populations by foreign antigen. Nat Immunol. 2005; 6(12):1219-27. DOI: 10.1038/ni1265. View

12.

Arpinati M, Green C, Heimfeld S, Heuser J, Anasetti C . Granulocyte-colony stimulating factor mobilizes T helper 2-inducing dendritic cells. Blood. 2001; 95(8):2484-90. View

13.

Buchsel P, Forgey A, Grape F, Hamann S . Granulocyte macrophage colony-stimulating factor: current practice and novel approaches. Clin J Oncol Nurs. 2002; 6(4):198-205. DOI: 10.1188/02.CJON.198-205. View

14.

Maldonado-Lopez R, De Smedt T, Pajak B, Heirman C, Thielemans K, Leo O . Role of CD8alpha+ and CD8alpha- dendritic cells in the induction of primary immune responses in vivo. J Leukoc Biol. 1999; 66(2):242-6. DOI: 10.1002/jlb.66.2.242. View

15.

Steinman R, Hawiger D, Nussenzweig M . Tolerogenic dendritic cells. Annu Rev Immunol. 2003; 21:685-711. DOI: 10.1146/annurev.immunol.21.120601.141040. View

16.

Hurst J, von Landenberg P . Toll-like receptors and autoimmunity. Autoimmun Rev. 2008; 7(3):204-8. DOI: 10.1016/j.autrev.2007.11.006. View

17.

Thornton A, Shevach E . CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med. 1998; 188(2):287-96. PMC: 2212461. DOI: 10.1084/jem.188.2.287. View

18.

OKeeffe M, Hochrein H, Vremec D, Pooley J, Evans R, Woulfe S . Effects of administration of progenipoietin 1, Flt-3 ligand, granulocyte colony-stimulating factor, and pegylated granulocyte-macrophage colony-stimulating factor on dendritic cell subsets in mice. Blood. 2002; 99(6):2122-30. DOI: 10.1182/blood.v99.6.2122. View

19.

Grohmann U, Fallarino F, Bianchi R, Belladonna M, Vacca C, Orabona C . IL-6 inhibits the tolerogenic function of CD8 alpha+ dendritic cells expressing indoleamine 2,3-dioxygenase. J Immunol. 2001; 167(2):708-14. DOI: 10.4049/jimmunol.167.2.708. View

20.

Maldonado-Lopez R, Maliszewski C, Urbain J, Moser M . Cytokines regulate the capacity of CD8alpha(+) and CD8alpha(-) dendritic cells to prime Th1/Th2 cells in vivo. J Immunol. 2001; 167(8):4345-50. DOI: 10.4049/jimmunol.167.8.4345. View