Desmoglein 3-specific T regulatory 1 cells consist of two subpopulations with differential expression of the transcription factor Foxp3.
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.
Veldman
Christian
C
Department of Dermatology, University of Marburg, Marburg, Germany. hertl@med.uni-marburg.de
Pahl
Andreas
A
Hertl
Michael
M
D015551:Autoimmunity / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D051184:Desmoglein 3 / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000276:immunology; D016376:Oligonucleotides, Antisense / Q000276:immunology; D010392:Pemphigus / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D016207:Cytokines; C071894:DSG3 protein, human; D051184:Desmoglein 3; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D016376:Oligonucleotides, Antisense
Nature. 2003 Jan 23;421(6921):388-92
12540904
Science. 2003 Feb 14;299(5609):1057-61
12522256
Nat Immunol. 2003 Apr;4(4):330-6
12612578
Nat Immunol. 2003 Apr;4(4):337-42
12612581
Transplantation. 2003 May 15;75(9 Suppl):8S-12S
12819483
N Engl J Med. 2003 Nov 13;349(20):1907-15
14614165
J Exp Med. 2003 Dec 15;198(12):1807-15
14676295
J Exp Med. 2003 Dec 15;198(12):1875-86
14676299
J Clin Invest. 2004 Feb;113(3):451-63
14755342
J Immunol. 2004 Mar 15;172(6):3883-92
15004196
J Immunol. 2004 May 1;172(9):5149-53
15100250
J Immunol. 2004 May 15;172(10):6468-75
15128839
Cell. 1991 Nov 29;67(5):869-77
1720352
J Clin Invest. 1992 Sep;90(3):919-26
1522242
Nature. 1992 Oct 22;359(6397):693-9
1436033
J Clin Invest. 1997 Jan 1;99(1):31-40
9011573
J Cell Biol. 1997 Jun 2;137(5):1091-102
9166409
Nature. 1997 Oct 16;389(6652):737-42
9338786
J Clin Invest. 1999 Feb;103(4):461-8
10021453
Blood. 2005 Feb 1;105(3):1162-9
15479730
J Exp Med. 2005 Apr 4;201(7):1061-7
15809351
Lancet. 2005 Jul 2-8;366(9479):61-73
15993235
Gene Ther. 2005 Sep;12(17):1294-304
15973443
J Clin Invest. 2005 Nov;115(11):3276-84
16211090
J Immunol. 2006 Mar 1;176(5):3215-22
16493082
Proc Natl Acad Sci U S A. 2006 Apr 25;103(17):6659-64
16617117
J Immunol. 2006 Sep 15;177(6):3806-13
16951342
Immunology. 2007 Mar;120(3):392-403
17239200
Science. 2007 Jul 13;317(5835):256-60
17569825
J Exp Med. 2007 Aug 6;204(8):1757-64
17620361
J Exp Med. 2007 Aug 6;204(8):1775-85
17620362
J Exp Med. 2007 Aug 6;204(8):1737-9
17620364
Nat Immunol. 2007 Sep;8(9):931-41
17694059
J Immunol. 2003 Jan 1;170(1):635-42
12496453
J Invest Dermatol. 2000 Jan;114(1):88-94
10620121
J Clin Invest. 2000 Mar;105(5):625-31
10712434
Nat Genet. 2001 Jan;27(1):68-73
11138001
Nat Med. 2001 Jan;7(1):114-8
11135625
J Immunol. 2001 May 1;166(9):5530-9
11313392
Skin Pharmacol Appl Skin Physiol. 2001 Nov-Dec;14(6):408-18
11598441
J Immunol. 2001 Dec 1;167(11):6312-20
11714795
J Exp Med. 2001 Dec 17;194(12):1711-9
11748273
J Exp Med. 2002 Mar 4;195(5):603-16
11877483
Br J Pharmacol. 2002 Apr;135(8):1915-26
11959794
Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6192-7
11972069
Eur J Immunol. 2002 Aug;32(8):2237-45
12209636