Intestinal IFN-?–producing type 1 regulatory T cells coexpress CCR5 and programmed cell death protein 1 and downregulate IL-10 in the inflamed guts of patients with inflammatory bowel disease - 06/11/18
Abstract |
Background |
IL-10 is an anti-inflammatory cytokine required for intestinal immune homeostasis. It mediates suppression of T-cell responses by type 1 regulatory T (TR1) cells but is also produced by CD25+ regulatory T (Treg) cells.
Objective |
We aimed to identify and characterize human intestinal TR1 cells and to investigate whether they are a relevant cellular source of IL-10 in patients with inflammatory bowel diseases (IBDs).
Methods |
CD4+ T cells isolated from the intestinal lamina propria of human subjects and mice were analyzed for phenotype, cytokine production, and suppressive capacities. Intracellular IL-10 expression by CD4+ T-cell subsets in the inflamed guts of patients with IBD (Crohn disease or ulcerative colitis) was compared with that in cells from noninflamed control subjects. Finally, the effects of proinflammatory cytokines on T-cell IL-10 expression were analyzed, and IL-1β and IL-23 responsiveness was assessed.
Results |
Intestinal TR1 cells could be identified by coexpression of CCR5 and programmed cell death protein 1 (PD-1) in human subjects and mice. CCR5+PD-1+ TR1 cells expressed IFN-γ and efficiently suppressed T-cell proliferation and transfer colitis. Intestinal IFN-γ+ TR1 cells, but not IL-7 receptor–positive TH cells or CD25+ Treg cells, showed lower IL-10 expression in patients with IBDs. TR1 cells were responsive to IL-23, and IFN-γ+ TR1 cells downregulated IL-10 with IL-1β and IL-23. Conversely, CD25+ Treg cells expressed higher levels of IL-1 receptor but showed stable IL-10 expression.
Conclusions |
We provide the first ex vivo characterization of human intestinal TR1 cells. Selective downregulation of IL-10 by IFN-γ+ TR1 cells in response to proinflammatory cytokines is likely to drive excessive intestinal inflammation in patients with IBDs.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : Inflammatory bowel disease, regulatory T cells, IL-10, IL-23
Abbreviations used : CD, CRC, DC, FACS, Foxp3, IBD, IL-1R, IL-7R, IL-23R, LAG3, PD-1, PMA, STAT, TR1, Treg, UC
Plan
| Supported by a long-term EMBO fellowship (to N.G.), and a short-term EMBO fellowship (to F.F.) and the Cariplo foundation (grant 2013-0937 to J.G., F.C. and R.A.F.). J.G., M.P., and F.C. are supported by the Italian Ministry of Health (projects RF-2011-02348920 and GR-2011-02352001). J.G. is supported by the AIRC foundation (grant IG 2015 Id.17448). INGM is supported by the Romeo ed Enrica Invernizzi foundation. R.A.F. is supported by the Howard Hughes Medical Institute. J.S.A. has attended the PhD program of Molecular Medicine of the University of Milan (UNIMI). |
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| Disclosure of potential conflict of interest: N. Gagliani's institution received a grant from Yale University for this work. M. Paroni's institution received a grant from the Ministry of Health (GR-2011-02352001) for this work. C. Frusteri is employed by IRCCS, Cà Granda Foundation, Ospedale Maggiore Policlinico, Gastroenterology and Endoscopy, Milan. S. Abrignani's institution received a grant from Fondazione Invernizzi for this work. J. Geginat's institution received grants from Cariplo Foundation and Ministry of Health for this work and from AISM, AIRC, Astellas, and Biotest AG for other works; he and his institution receive consultancy fees from Biotest AG. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 142 - N° 5
P. 1537 - novembre 2018 Retour au numéro
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