Intravenous Apoptotic Spleen Cell Infusion Induces a TGF-beta-dependent Regulatory T-cell Expansion

Overview

Journal Cell Death Differ

Specialty Cell Biology

Date 2005 Jun 18

PMID 15962005

Citations 72

Authors

F Kleinclauss

S Perruche

E Masson

M De Carvalho Bittencourt

S Biichle

J-P Remy-Martin

C Ferrand

M Martin

H Bittard

J-M Chalopin

E Seilles

P Tiberghien

P Saas

Affiliations

Soon will be listed here.

Abstract

Apoptotic leukocytes are endowed with immunomodulatory properties that can be used to enhance hematopoietic engraftment and prevent graft-versus-host disease (GvHD). This apoptotic cell-induced tolerogenic effect is mediated by host macrophages and not recipient dendritic cells or donor phagocytes present in the bone marrow graft as evidenced by selective cell depletion and trafficking experiments. Furthermore, apoptotic cell infusion is associated with TGF-beta-dependent donor CD4+CD25+ T-cell expansion. Such cells have a regulatory phenotype (CD62L(high) and intracellular CTLA-4+), express high levels of forkhead-box transcription factor p3 (Foxp3) mRNA and exert ex vivo suppressive activity through a cell-to-cell contact mechanism. In vivo CD25 depletion after apoptotic cell infusion prevents the apoptotic cell-induced beneficial effects on engraftment and GvHD occurrence. This highlights the role of regulatory T cells in the tolerogenic effect of apoptotic cell infusion. This novel association between apoptosis and regulatory T-cell expansion may also contribute to preventing deleterious autoimmune responses during normal turnover.

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References

Chen W, Jin W, Hardegen N, Lei K, Li L, Marinos N . Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med. 2003; 198(12):1875-86. PMC: 2194145. DOI: 10.1084/jem.20030152. View

Albert M . Death-defying immunity: do apoptotic cells influence antigen processing and presentation?. Nat Rev Immunol. 2004; 4(3):223-31. DOI: 10.1038/nri11308. View

Fantini M, Becker C, Monteleone G, Pallone F, Galle P, Neurath M . Cutting edge: TGF-beta induces a regulatory phenotype in CD4+CD25- T cells through Foxp3 induction and down-regulation of Smad7. J Immunol. 2004; 172(9):5149-53. DOI: 10.4049/jimmunol.172.9.5149. View

Apostolou I, von Boehmer H . In vivo instruction of suppressor commitment in naive T cells. J Exp Med. 2004; 199(10):1401-8. PMC: 2211808. DOI: 10.1084/jem.20040249. View

Perruche S, Kleinclauss F, Bittencourt M, Paris D, Tiberghien P, Saas P . Intravenous infusion of apoptotic cells simultaneously with allogeneic hematopoietic grafts alters anti-donor humoral immune responses. Am J Transplant. 2004; 4(8):1361-5. DOI: 10.1111/j.1600-6143.2004.00509.x. View

Fu S, Zhang N, Yopp A, Chen D, Mao M, Chen D . TGF-beta induces Foxp3 + T-regulatory cells from CD4 + CD25 - precursors. Am J Transplant. 2004; 4(10):1614-27. DOI: 10.1111/j.1600-6143.2004.00566.x. View

Groux H, OGarra A, Bigler M, Rouleau M, Antonenko S, De Vries J . A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature. 1997; 389(6652):737-42. DOI: 10.1038/39614. View

Voll R, Herrmann M, Roth E, Stach C, Kalden J, Girkontaite I . Immunosuppressive effects of apoptotic cells. Nature. 1997; 390(6658):350-1. DOI: 10.1038/37022. 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

10.

Leenen P, Radosevic K, Voerman J, Salomon B, van Rooijen N, Klatzmann D . Heterogeneity of mouse spleen dendritic cells: in vivo phagocytic activity, expression of macrophage markers, and subpopulation turnover. J Immunol. 1998; 160(5):2166-73. View

11.

Letterio J, Roberts A . Regulation of immune responses by TGF-beta. Annu Rev Immunol. 1998; 16:137-61. DOI: 10.1146/annurev.immunol.16.1.137. View

12.

Gao Y, Herndon J, Zhang H, Griffith T, Ferguson T . Antiinflammatory effects of CD95 ligand (FasL)-induced apoptosis. J Exp Med. 1998; 188(5):887-96. PMC: 2213381. DOI: 10.1084/jem.188.5.887. View

13.

Sun E, Gao Y, Chen J, Roberts A, Wang X, Chen Z . Allograft tolerance induced by donor apoptotic lymphocytes requires phagocytosis in the recipient. Cell Death Differ. 2004; 11(12):1258-64. DOI: 10.1038/sj.cdd.4401500. View

14.

Taylor P, Panoskaltsis-Mortari A, Swedin J, Lucas P, Gress R, Levine B . L-Selectin(hi) but not the L-selectin(lo) CD4+25+ T-regulatory cells are potent inhibitors of GVHD and BM graft rejection. Blood. 2004; 104(12):3804-12. DOI: 10.1182/blood-2004-05-1850. View

15.

Colson Y, Christopher K, Glickman J, Taylor K, Wright R, Perkins D . Absence of clinical GVHD and the in vivo induction of regulatory T cells after transplantation of facilitating cells. Blood. 2004; 104(12):3829-35. DOI: 10.1182/blood-2004-01-0393. View

16.

Perruche S, Kleinclauss F, Lienard A, Robinet E, Tiberghien P, Saas P . A single-platform approach using flow cytometry and microbeads to evaluate immune reconstitution in mice after bone marrow transplantation. J Immunol Methods. 2004; 294(1-2):53-66. DOI: 10.1016/j.jim.2004.08.011. View

17.

Liang S, Alard P, Zhao Y, Parnell S, Clark S, Kosiewicz M . Conversion of CD4+ CD25- cells into CD4+ CD25+ regulatory T cells in vivo requires B7 costimulation, but not the thymus. J Exp Med. 2005; 201(1):127-37. PMC: 2212775. DOI: 10.1084/jem.20041201. View

18.

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

19.

Steinman R, Turley S, Mellman I, Inaba K . The induction of tolerance by dendritic cells that have captured apoptotic cells. J Exp Med. 2000; 191(3):411-6. PMC: 2195815. DOI: 10.1084/jem.191.3.411. View

20.

Huang F, Platt N, Wykes M, Major J, Powell T, Jenkins C . A discrete subpopulation of dendritic cells transports apoptotic intestinal epithelial cells to T cell areas of mesenteric lymph nodes. J Exp Med. 2000; 191(3):435-44. PMC: 2195813. DOI: 10.1084/jem.191.3.435. View