Enhanced suppressor function of TIM-3+ FoxP3+ regulatory T cells.
T-cell immunoglobulin and mucin domain 3 (TIM-3) is an Ig-superfamily member expressed on IFN-γ-secreting Th1 and Tc1 cells and was identified as a negative regulator of immune tolerance. TIM-3 is expressed by a subset of activated CD4(+) T cells, and anti-CD3/anti-CD28 stimulation increases both the level of expression and the number of TIM-3(+) T cells. In mice, TIM-3 is constitutively expressed on natural regulatory T (Treg) cells and has been identified as a regulatory molecule of alloimmunity through its ability to modulate CD4(+) T-cell differentiation. Here, we examined TIM-3 expression on human Treg cells to determine its role in T-cell suppression. In contrast to mice, TIM-3 is not expressed on Treg cells ex vivo but is upregulated after activation. While TIM-3(+) Treg cells with increased gene expression of LAG3, CTLA4, and FOXP3 are highly efficient suppressors of effector T (Teff) cells, TIM-3(-) Treg cells poorly suppressed Th17 cells as compared with their suppression of Th1 cells; this decreased suppression ability was associated with decreased STAT-3 expression and phosphorylation and reduced gene expression of IL10, EBI3, GZMB, PRF1, IL1Rα, and CCR6. Thus, our results suggest that TIM-3 expression on Treg cells identifies a population highly effective in inhibiting pathogenic Th1- and Th17-cell responses.
Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT 06520.
Anne-Sophie
AS
Gautron
Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT 06520.
Margarita
M
Dominguez-Villar
Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT 06520.
Marine
M
de Marcken
Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT 06520.
David A
DA
Hafler
D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D060908:CTLA-4 Antigen / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology*; D053804:Granzymes / Q000276:immunology; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology; D007378:Interleukins / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000276:immunology*; D051379:Mice; D015778:Minor Histocompatibility Antigens; D054399:Receptors, CCR6 / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology*; D000093322:Lymphocyte Activation Gene 3 Protein
D015703:Antigens, CD; C106311:CCR6 protein, human; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C097732:EBI3 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; C508609:IL10 protein, human; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007378:Interleukins; D008565:Membrane Proteins; D015778:Minor Histocompatibility Antigens; D054399:Receptors, CCR6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D016753:Interleukin-10; C509213:GZMB protein, human; D053804:Granzymes; D000093322:Lymphocyte Activation Gene 3 Protein
FoxP3; Regulatory T (Treg) cells; TIM-3; Th17