2B4 controls gut immune homeostasis by promoting IL-1β expression in Ly6Chigh monocytes that trigger IL-22/IL-18-mediated epithelial regeneration

Abstract Impaired signaling, downstream of 2B4, is associated with colitis in human patients with XLP ; however, the precise mechanism by which 2B4 maintains gut integrity remains unknown. In dextran sodium sulfate (DSS)-fed reciprocal chimera mice, massive tissue destruction was observed due to lack of 2B4 in hematopoietic compartments, in particular Ly6ChighCD11b+ monocyte subsets within the lamina propria leukocytes. Not only did the number of Ly6ChighCD11b+ monocytes get significantly reduced, their intrinsic capacity to produce IL-1β during DSS stimulation was also drastically impaired in 2B4−/− mice. These defects led to an impaired IL-22 secretion in ILCs and IL-18 production in gut epithelial cells in the 2B4−/− mice. Furthermore, severe inflammatory phenotypes seen in 2B4−/− mice could only be rescued by adoptive transfer of Ly6ChighCD11b+ monocytes, but not with BMDC or NK cells. Therefore, 2B4 functions as an important receptor in inflammatory monocytes in response to commensal microbiota during acute colonic inflammation.