Gliadin-reactive vitamin D-sensitive proinflammatory ILCPs are enriched in celiac patients

Celiac disease (CD) is a multisystem disease in which different organs may be affected. We investigate whether circulating innate lymphoid cells (ILCs) contribute to the CD peripheral inflammatory status. We find that the CD cytokine profile is characterized by high concentrations of IL-12p40, IL-18, and IFN-γ, paralleled by an expansion of ILC precursors (ILCPs). In the presence of the gliadin peptides p31–43 and pα-9, ILCPs from CD patients increase transglutaminase 2 (TG2) expression, produce IL-18 and IFN-γ, and stimulate CD4+ T lymphocytes. IFN-γ is also produced upon stimulation with IL-12p40 and IL-18 and is inhibited by the addition of vitamin D. Low levels of blood vitamin D correlate with high IFN-γ and ILCP presence and mark the CD population mostly affected by extraintestinal symptoms. Dietary vitamin D supplementation appears to be an interesting therapeutic approach to dampen ILCP-mediated IFN-γ production. [Display omitted] •ILCPs are enriched in the peripheral blood of celiac patients•ILCPs react to gliadin peptides by producing cytokines and stimulating T cells•ILCP production of IFN-γ can be inhibited by vitamin D•High IFN-γ and low vitamin D correlate with more extraintestinal symptoms Ercolano et al. illustrate how gliadin peptide-driven ILCP activation contributes to the peripheral, extraintestinal inflammation characterizing celiac patients. ILCP activation is dampened by vitamin D, which is low in patients experiencing severe systemic inflammation and showing more extraintestinal symptoms.