Friday, July 17, 2015: 11:00 AM
Salon 7, Ground Floor (Maritim Hotel)
Dror Shouval, MD
,
Boston Children's Hospital, Boston, MA, United States
Alexandra Griffith
,
Boston Children's Hospital, Boston, MA
Athos Bousvaros
,
Boston Children's Hospital, Boston, MA
Batya Weiss
,
Edmond and Lily Safra Children’s Hospital, Tel Hashomer, Israel
Raz Somech
,
Edmond and Lily Safra Children’s Hospital, Tel Hashomer, Israel
Anthony Loizides
,
Children's Hospital at Montefiore, Bronx, NY
Tadahiro Yanagi
,
Kurume University School of Medicine, Kurume, Japan
Fernanda Minafra
,
Federal University of Minas Gerais, Minas Gerais, Brazil
Rita Beier
,
Hanover Medical School, Hanover, Germany
Mary Sherlock
,
McMaster Children’s Hospital, West Hamilton, ON, Canada
Christoph Klein
,
Dr von Hauner Children’s Hospital, Munich, Germany
Aleixo Muise
,
Hospital for Sick Children, Toronto, QC, Canada
Scott Snapper, MD, PhD
,
Brigham and Women's Hospital, Boston, MA
Background: Loss of function mutations in the IL10 receptor (IL10R) genes cause severe infantile IBD. We have recently reported that innate immune IL10R signaling is a key regulator of intestinal immune response and anti-inflammatory macrophage generation in mice and humans. Other groups have demonstrated in mice that IL10R signaling is required for both normal suppressive function of T regulatory cells (Tregs) and for prevention of T effector cell-mediated colitis. The goal of the current study was to define whether IL10R signaling modulates T cells responses in humans.
Results: Analysis of seven IL10R-deficient patients demonstrated similar frequencies of peripheral blood and colonic lamina propria FoxP3+ Tregs, compared to control healthy subjects. Moreover, IL10R-deficient peripheral blood Tregs suppressed the proliferation of T naïves, comparable to control Tregs. The generation of Tregs from control and IL10R-deficient T naïve cells was also similar, suggesting that the generation and in-vitro function of Tregs is normal in IL10R-deficient patients. However, IL10R-deficient T naïves exhibited significantly higher proliferative capacity, and a marked increase in the generation of Th17 cells, compared to T naïves from control subjects. Moreover, IL10R-deficient patients had increased numbers of Th17 cells in the intestinal lamina propria.
Conclusions: IL10R signaling regulates Th17 generation and T cell proliferation in humans, while it does not appear to regulate the generation of Tregs in blood and mucosal compartments. Furthermore, in-vitro Treg suppression is not dependent on IL10R signaling. Therapies targeting the Th17 axis might be beneficial for IL10R-deficient patients as a bridge to stem cell transplantation.
