Innate Lymphoid Cells Groups 1 and 3 in the Epithelial Compartment of Functional Human Intestinal Allografts

We examined intraepithelial lymphocytes (IELs) in 213 ileal biopsies from 16 bowel grafts and compared them with 32 biopsies from native intestines. During the first year posttransplantation, grafts exhibited low levels of IELs (percentage of CD103(+) cells) principally due to reduced CD3(+)CD8(+) cells, while CD103(+)CD3(-) cell numbers became significantly higher. Changes in IEL subsets did not correlate with histology results, isolated intestine, or multivisceral transplants, but CD3(-) IELs were significantly higher in patients receiving corticosteroids. Compared with controls, more CD3(-) IELs of the grafts expressed CD56, NKp44, interleukin (IL)-23 receptor, retinoid-related orphan receptor gamma t (ROR gamma t), and CCR6. No difference was observed in granzyme B, and CD3(-)CD127(+) cells were more abundant in native intestines. Ex vivo, and after in vitro activation, CD3(-) IELs in grafts produced significantly more interferon (IFN)-gamma and IL-22, and a double IFN gamma+IL-22(+) population was observed. Epithelial cell-depleted grafts IELs were cytotoxic, whereas this was not observed in controls. In conclusion, different from native intestines, a CD3(-) IEL subset predominates in grafts, showing features of natural killer cells and intraepithelial ILC1 (CD56(+), NKp44(+), CCR6(+), CD127(-) , cytotoxicity, and IFN gamma secretion), ILC3 (CD56(+), NKp44(+), IL-23R(+), CCR6(+), ROR gamma t(+), and IL-22 secretion), and intermediate ILC1-ILC3 phenotypes (IFN gamma+IL-22(+)). Viability of intestinal grafts may depend on the balance among proinflammatory and homeostatic roles of ILC subsets.