IL-15 AND NOTCH DRIVE THE DIFFERENTIATION OF A NEW SUBSET OF GUT INNATE LYMPHOID CELLS

Recent work has highlighted how a spectrum of innate lymphoid cells (ILC) present in the intestinal lamina propria play a key role in the complex network of innate and adaptive immune mechanisms that control intestinal homeostasis and protect the gut against pathogens. Herein we intend to characterize a yet poorly defined population of ILC present in the gut epithelium and which may be the cellular origin of the rare and unusual lymphoma that complicates celiac disease (CD). They also represent approximately 50% of the intraepithelial lymphocytes at birth, pointing to a possible role in local defense when adaptive intestinal immunity is still weak. Our data indicate that those intraepithelial ILC (IE-ILC) form a distinctive subset of ILC both in human and mouse characterized by their expression of the CD103 integrin, the presence of intracellular CD3 chains (iCD3+) which remains absent from the surface CD3 (sCD3-) and the presence of TCR rearrangements. This subset has overlapping features with NK cells and a strong dependence on interleukin-15 (IL-15) for their maintenance and their differentiation. In addition, we have deciphered the mechanism, by which IL-15 blocks the differentiation of lymphoid precursors into T cells and promotes their development into cytotoxic IE-ILC.