Human group3 innate lymphoid cells express DR3 and respond to TL1A with enhanced IL-22 production and IL-2-dependent proliferation

摘要

Death receptor 3 (DR3, TNFRSF25) is expressed by activated lymphocytes and signaling by its ligand, TL1A, enhances cytokine expression and proliferation. Recent studies show that DR3 is also present on murine type 2 innate lymphoid cells (ILC25). Here, we show that DR3 is expressed by IL-22-producing human group 3 innate lymphoid cells (ILC35). Stimulation of ILC35 with exogenous TL1A alone had no impact on cytokine production or proliferation. Addition of TL1A to IL-1 beta IL-23 significantly enhanced the amount IL-22 produced by ILC35 as well as the percentage IL-22- and IL-8-producing cells. Addition of TL1A to IL-1 beta IL-23 also augmented ILC3 proliferation. Mechanistically, this occurred through the upregulation of CD25 and responsiveness to IL-2 stimulation. The combination of TL1A, IL-1 beta+ IL-23, and IL-2 expanded ILC35 while IL-1 beta+ IL-23 did not increase proliferation above controls. After 2 weeks of expansion, ILC35 maintained their phenotype, transcription factor expression, and function (IL-22 production). These findings identify DR3 as a costimulatory molecule on ILC35 that could be exploited for ex vivo expansion and clinical use.