Gliadin-specific type 1 regulatory T cells from the intestinal mucosa of treated celiac patients inhibit pathogenic T cells.
Celiac disease (CD) results from a permanent intolerance to dietary gluten and is due to a massive T cell-mediated immune response to gliadin, the main component of gluten. In this disease, the regulation of immune responses to dietary gliadin is altered. Herein, we investigated whether IL-10 could modulate anti-gliadin immune responses and whether gliadin-specific type 1 regulatory T (Tr1) cells could be isolated from the intestinal mucosa of CD patients in remission. Short-term T cell lines were generated from jejunal biopsies, either freshly processed or cultured ex vivo with gliadin in the presence or absence of IL-10. Ex vivo stimulation of CD biopsies with gliadin in the presence of IL-10 resulted in suppression of Ag-specific proliferation and cytokine production, indicating that pathogenic T cells are susceptible to IL-10-mediated immune regulation. T cell clones generated from intestinal T cell lines were tested for gliadin specificity by cytokine production and proliferative responses. The majority of gliadin-specific T cell clones had a Th0 cytokine production profile with secretion of IL-2, IL-4, IFN-gamma, and IL-10 and proliferated in response to gliadin. Tr1 cell clones were also isolated. These Tr1 cells were anergic, restricted by DQ2 (a CD-associated HLA), and produced IL-10 and IFN-gamma, but little or no IL-2 or IL-4 upon activation with gliadin or polyclonal stimuli. Importantly, gliadin-specific Tr1 cell clones suppressed proliferation of pathogenic Th0 cells. In conclusion, dietary Ag-specific Tr1 cells are present in the human intestinal mucosa, and strategies to boost their numbers and/or function may offer new therapeutic opportunities to restore gut homeostasis.
Gianfrani
Carmen
C
Institute of Food Science-Consiglio Nazionale delle Ricerche, Avellino, Italy. cgianfrani@isa.cnr.it
Levings
Megan K
MK
Sartirana
Claudia
C
Mazzarella
Giuseppe
G
Barba
Gianvincenzo
G
Zanzi
Delia
D
Camarca
Alessandra
A
Iaquinto
Gaetano
G
Giardullo
Nicola
N
Auricchio
Salvatore
S
Troncone
Riccardo
R
Roncarolo
Maria-Grazia
MG
D000293:Adolescent; D000328:Adult; D002446:Celiac Disease / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D049109:Cell Proliferation; D002648:Child; D002999:Clone Cells; D016207:Cytokines / Q000096:biosynthesis; D004044:Dietary Proteins / Q000276:immunology; D005260:Female; D005903:Gliadin / Q000276:immunology*; D006131:Growth Inhibitors / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D016753:Interleukin-10 / Q000502:physiology; D007413:Intestinal Mucosa / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009924:Organ Culture Techniques; D050378:T-Lymphocytes, Regulatory / Q000145:classification / Q000276:immunology* / Q000378:metabolism
D016207:Cytokines; D004044:Dietary Proteins; D006131:Growth Inhibitors; D016753:Interleukin-10; D005903:Gliadin