Type 3 Innate Lymphoid Cells Are Associated With A Successful Intestinal Transplant

Although innate lymphoid cells (ILCs) play fundamental roles in mucosal barrier functionality and tissue homeostasis, ILC-related mechanisms underlying intestinal barrier function, homeostatic regulation, and graft rejection in intestinal transplantation (ITx) patients have yet to be thoroughly defined. We foundprotectivetype 3 NKp44(+)ILCs (ILC3s) to be significantly diminished in newly transplanted allografts, compared to allografts at 6 months, whereasproinflammatorytype 1 NKp44(-)ILCs (ILC1s) were higher. Moreover, serial immunomonitoring revealed that inhealthyallografts,protectiveILC3s repopulate by 2-4 weeks postoperatively, but in rejecting allografts they remain diminished. Intracellular cytokine staining confirmed that NKp44(+)ILC3 produced protective interleukin-22 (IL-22), whereas ILC1s produced proinflammatory interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha). Our findings about the paucity ofprotectiveILC3s immediately following transplant and their repopulation in healthy allografts during the first month following transplant were confirmed by RNA-sequencing analyses of serial ITx biopsies. Overall, our findings show that ILCs may play a key role in regulating ITx graft homeostasis and could serve as sentinels for early recognition of allograft rejection and be targets for future therapies.