Desmoglein 3-specific T Regulatory 1 Cells Consist of Two Subpopulations with Differential Expression of the Transcription Factor Foxp3

Overview

Journal Immunology

Specialty Allergy & Immunology

Date 2008 Sep 20

PMID 18800988

Citations 6

Authors

Christian Veldman

Andreas Pahl

Michael Hertl

Affiliations

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Abstract

Pemphigus vulgaris (PV) is an autoimmune bullous skin disorder associated with autoantibodies against desmoglein (Dsg) 3. An imbalance of type 1 regulatory T (Tr1) cells and T helper type 2 (Th2) cells specific for Dsg3 may be critical for the loss of tolerance against Dsg3 in PV. Within the population of Dsg3-responsive, interleukin (IL)-10-secreting Tr1 cell clones, two major subpopulations were identified and sorted by fluorescence-activated cell sorting (FACS) based on their size and granularity. Upon in vitro culture, the larger subpopulation differentiated back into the two former subpopulations of the Tr1 cell clones, while the smaller subpopulation died within 2 weeks. The smaller subpopulation of the Tr1 cell clones was characterized by the expression of Foxp3, the secretion of IL-10, transforming growth factor (TGF)-beta and IL-5 upon stimulation with Dsg3, a proliferative response to IL-2 but not to Dsg3 or mitogenic stimuli, and an inhibitory effect on the proliferative response of Dsg3-responsive Th clones in a Dsg3-specific manner. In contrast, the larger subpopulation showed a Th-like phenotype, lacking Foxp3, cytotoxic T-lymphocyte antigen 4 (CTLA4) and glucocorticoid-induced tumour necrosis factor receptor (GITR) expression and IL-2 secretion, and did not mount a proliferative response to Dsg3 and mitogenic stimuli. The two Tr1 subpopulations showed expression of identical T-cell receptor (TCR) V beta chains which varied among the PV patients studied. Upon inhibition of Foxp3, the smaller Tr1 subpopulation developed a proliferate response to Dsg3 and mitogenic stimuli, no longer suppressed Dsg3-specific Th cells, lost expression of GITR and CTLA4 and secreted IL-2. Thus, our observations suggest a distinct relationship between Dsg3-specific Tr1 and Th-like cells which may be critical for the continuous generation and survival of Dsg3-specific Tr1 cells.

Citing Articles

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References

Kemper C, Chan A, Green J, Brett K, Murphy K, Atkinson J . Activation of human CD4+ cells with CD3 and CD46 induces a T-regulatory cell 1 phenotype. Nature. 2003; 421(6921):388-92. DOI: 10.1038/nature01315. View

Hori S, Nomura T, Sakaguchi S . Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003; 299(5609):1057-61. DOI: 10.1126/science.1079490. View

Fontenot J, Gavin M, Rudensky A . Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol. 2003; 4(4):330-6. DOI: 10.1038/ni904. View

Khattri R, Cox T, Yasayko S, Ramsdell F . An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol. 2003; 4(4):337-42. DOI: 10.1038/ni909. View

Groux H . Type 1 T-regulatory cells: their role in the control of immune responses. Transplantation. 2003; 75(9 Suppl):8S-12S. DOI: 10.1097/01.TP.0000067944.90241.BD. View

Kremer J, Westhovens R, Leon M, Di Giorgio E, Alten R, Steinfeld S . Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. N Engl J Med. 2003; 349(20):1907-15. DOI: 10.1056/NEJMoa035075. View

Li J, Huston G, Swain S . IL-7 promotes the transition of CD4 effectors to persistent memory cells. J Exp Med. 2003; 198(12):1807-15. PMC: 2194161. DOI: 10.1084/jem.20030725. View

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

Arif S, Tree T, Astill T, Tremble J, Bishop A, Dayan C . Autoreactive T cell responses show proinflammatory polarization in diabetes but a regulatory phenotype in health. J Clin Invest. 2004; 113(3):451-63. PMC: 324541. DOI: 10.1172/JCI19585. View

10.

Veldman C, Gebhard K, Uter W, Wassmuth R, Grotzinger J, Schultz E . T cell recognition of desmoglein 3 peptides in patients with pemphigus vulgaris and healthy individuals. J Immunol. 2004; 172(6):3883-92. DOI: 10.4049/jimmunol.172.6.3883. View

11.

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

12.

Veldman C, Hohne A, Dieckmann D, Schuler G, Hertl M . Type I regulatory T cells specific for desmoglein 3 are more frequently detected in healthy individuals than in patients with pemphigus vulgaris. J Immunol. 2004; 172(10):6468-75. DOI: 10.4049/jimmunol.172.10.6468. View

13.

Amagai M, Stanley J . Autoantibodies against a novel epithelial cadherin in pemphigus vulgaris, a disease of cell adhesion. Cell. 1991; 67(5):869-77. DOI: 10.1016/0092-8674(91)90360-b. View

14.

Amagai M, Karpati S, Prussick R, Stanley J . Autoantibodies against the amino-terminal cadherin-like binding domain of pemphigus vulgaris antigen are pathogenic. J Clin Invest. 1992; 90(3):919-26. PMC: 329947. DOI: 10.1172/JCI115968. View

15.

Shull M, Ormsby I, Kier A, Pawlowski S, Diebold R, Yin M . Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature. 1992; 359(6397):693-9. PMC: 3889166. DOI: 10.1038/359693a0. View

16.

Lin M, Swartz S, Lopez A, Ding X, Fernandez-Vina M, Stastny P . Development and characterization of desmoglein-3 specific T cells from patients with pemphigus vulgaris. J Clin Invest. 1997; 99(1):31-40. PMC: 507764. DOI: 10.1172/JCI119130. View

17.

Koch P, Mahoney M, Ishikawa H, Pulkkinen L, Uitto J, Shultz L . Targeted disruption of the pemphigus vulgaris antigen (desmoglein 3) gene in mice causes loss of keratinocyte cell adhesion with a phenotype similar to pemphigus vulgaris. J Cell Biol. 1997; 137(5):1091-102. PMC: 2136216. DOI: 10.1083/jcb.137.5.1091. View

18.

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

19.

Mahoney M, Wang Z, Rothenberger K, Koch P, Amagai M, Stanley J . Explanations for the clinical and microscopic localization of lesions in pemphigus foliaceus and vulgaris. J Clin Invest. 1999; 103(4):461-8. PMC: 408100. DOI: 10.1172/JCI5252. View

20.

Levings M, Gregori S, Tresoldi E, Cazzaniga S, Bonini C, Roncarolo M . Differentiation of Tr1 cells by immature dendritic cells requires IL-10 but not CD25+CD4+ Tr cells. Blood. 2004; 105(3):1162-9. DOI: 10.1182/blood-2004-03-1211. View