Uptake of Apoptotic DC Converts Immature DC into Tolerogenic DC That Induce Differentiation of Foxp3+ Treg

Overview

Journal Eur J Immunol

Specialty Allergy & Immunology

Date 2010 Jan 27

PMID 20101618

Citations 79

Authors

Rahul Kushwah

Jing Wu

Jordan R Oliver

George Jiang

Jinyi Zhang

Katherine A Siminovitch

Jim Hu

Affiliations

Soon will be listed here.

Abstract

DC apoptosis has been observed in patients with cancer and sepsis, and defects in DC apoptosis have been implicated in the development of autoimmune diseases. However, the mechanisms of how DC apoptosis affects immune responses, are unclear. In this study, we showed that immature viable DC have the ability to uptake apoptotic DC as well as necrotic DC without it being recognized as an inflammatory event by immature viable DC. However, the specific uptake of apoptotic DC converted immature viable DC into tolerogenic DC, which were resistant to LPS-induced maturation. These tolerogenic DC secreted increased levels of TGF-beta1, which induced differentiation of naïve T cells into Foxp3(+) Treg. Furthermore, induction of Treg differentiation only occurred upon uptake of apoptotic DC and not apoptotic splenocytes by viable DC, indicating that it is specifically the uptake of apoptotic DC that gives viable immature DC the potential to induce Foxp3(+) Treg. Taken together, these findings identify uptake of apoptotic DC by viable immature DC as an immunologically tolerogenic event.

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References

Williams C, Harry R, McLeod J . Apoptotic cells induce dendritic cell-mediated suppression via interferon-gamma-induced IDO. Immunology. 2007; 124(1):89-101. PMC: 2434374. DOI: 10.1111/j.1365-2567.2007.02743.x. View

Walsh C, Wen B, Chinnaiyan A, ORourke K, Dixit V, Hedrick S . A role for FADD in T cell activation and development. Immunity. 1998; 8(4):439-49. DOI: 10.1016/s1074-7613(00)80549-x. View

Pinzon-Charry A, Maxwell T, McGuckin M, Schmidt C, Furnival C, Lopez J . Spontaneous apoptosis of blood dendritic cells in patients with breast cancer. Breast Cancer Res. 2006; 8(1):R5. PMC: 1413992. DOI: 10.1186/bcr1361. View

Fadok V, Bratton D, Konowal A, Freed P, Westcott J, Henson P . Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest. 1998; 101(4):890-8. PMC: 508637. DOI: 10.1172/JCI1112. View

Park Y, Lee S, Sung Y . Cutting Edge: CpG DNA inhibits dendritic cell apoptosis by up-regulating cellular inhibitor of apoptosis proteins through the phosphatidylinositide-3'-OH kinase pathway. J Immunol. 2001; 168(1):5-8. DOI: 10.4049/jimmunol.168.1.5. View

Hotchkiss R, Karl I . The pathophysiology and treatment of sepsis. N Engl J Med. 2003; 348(2):138-50. DOI: 10.1056/NEJMra021333. View

Feng H, Zeng Y, Graner M, Katsanis E . Stressed apoptotic tumor cells stimulate dendritic cells and induce specific cytotoxic T cells. Blood. 2002; 100(12):4108-15. DOI: 10.1182/blood-2002-05-1389. View

Wu J, Duan R, Cao H, Field D, Newnham C, Koehler D . Regulation of epithelium-specific Ets-like factors ESE-1 and ESE-3 in airway epithelial cells: potential roles in airway inflammation. Cell Res. 2008; 18(6):649-63. PMC: 4494831. DOI: 10.1038/cr.2008.57. View

Tinsley K, Grayson M, Swanson P, Drewry A, Chang K, Karl I . Sepsis induces apoptosis and profound depletion of splenic interdigitating and follicular dendritic cells. J Immunol. 2003; 171(2):909-14. DOI: 10.4049/jimmunol.171.2.909. View

10.

Takahashi M, Kobayashi Y . Cytokine production in association with phagocytosis of apoptotic cells by immature dendritic cells. Cell Immunol. 2004; 226(2):105-15. DOI: 10.1016/j.cellimm.2003.11.008. View

11.

Winau F, Weber S, Sad S, de Diego J, Hoops S, Breiden B . Apoptotic vesicles crossprime CD8 T cells and protect against tuberculosis. Immunity. 2006; 24(1):105-17. DOI: 10.1016/j.immuni.2005.12.001. View

12.

Kushwah R, Cao H, Hu J . Characterization of pulmonary T cell response to helper-dependent adenoviral vectors following intranasal delivery. J Immunol. 2008; 180(6):4098-108. DOI: 10.4049/jimmunol.180.6.4098. View

13.

Pinzon-Charry A, Ho C, Maxwell T, McGuckin M, Schmidt C, Furnival C . Numerical and functional defects of blood dendritic cells in early- and late-stage breast cancer. Br J Cancer. 2007; 97(9):1251-9. PMC: 2360464. DOI: 10.1038/sj.bjc.6604018. View

14.

Peng Y, Martin D, Kenkel J, Zhang K, Ogden C, Elkon K . Innate and adaptive immune response to apoptotic cells. J Autoimmun. 2007; 29(4):303-9. PMC: 2100400. DOI: 10.1016/j.jaut.2007.07.017. 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.

Chen M, Wang Y, Wang Y, Huang L, Sandoval H, Liu Y . Dendritic cell apoptosis in the maintenance of immune tolerance. Science. 2006; 311(5764):1160-4. DOI: 10.1126/science.1122545. View

17.

Chen X, Doffek K, Sugg S, Shilyansky J . Phosphatidylserine regulates the maturation of human dendritic cells. J Immunol. 2004; 173(5):2985-94. DOI: 10.4049/jimmunol.173.5.2985. View

18.

Newton K, Harris A, Bath M, Smith K, Strasser A . A dominant interfering mutant of FADD/MORT1 enhances deletion of autoreactive thymocytes and inhibits proliferation of mature T lymphocytes. EMBO J. 1998; 17(3):706-18. PMC: 1170420. DOI: 10.1093/emboj/17.3.706. View

19.

Monneret G, Debard A, Venet F, Bohe J, Hequet O, Bienvenu J . Marked elevation of human circulating CD4+CD25+ regulatory T cells in sepsis-induced immunoparalysis. Crit Care Med. 2003; 31(7):2068-71. DOI: 10.1097/01.CCM.0000069345.78884.0F. View

20.

De S, Ajmone-Cat M, Nicolini A, Minghetti L . Expression of phosphatidylserine receptor and down-regulation of pro-inflammatory molecule production by its natural ligand in rat microglial cultures. J Neuropathol Exp Neurol. 2002; 61(3):237-44. DOI: 10.1093/jnen/61.3.237. View