Interleukin-1β Selectively Expands and Sustains Interleukin-22+ Immature Human Natural Killer Cells in Secondary Lymphoid Tissue

Among human natural killer (NK) cell intermediates in secondary lymphoid tissue (SLT), stage 3 CD34(-)CD117(+)CD161(+)CD94(-) immature NK (iNK) cells uniquely express aryl hydrocarbon receptor (AHR) and interleukin-22 (IL-22), supporting a role in mucosal immunity. The mechanisms controlling proliferation and differentiation of these cells are unknown. Here we demonstrate that the IL-1 receptor IL-1R1 was selectively expressed by a subpopulation of iNK cells that localized proximal to IL-1 beta-producing conventional dendritic cells (cDCs) within SLT. IL-1R1(hi) iNK cells required continuous exposure to IL-1 beta to retain AHR and IL-22 expression, and they proliferate in direct response to cDC-derived IL-15 and IL-1 beta. In the absence of IL-1 beta, a substantially greater fraction of IL-1R1(hi) iNK cells differentiated to stage 4 NK cells and acquired the ability to kill and secrete IFN-gamma. Thus, cDC-derived IL-1 beta preserves and expands IL-1R1(hi) IL-22(+)AHR(+) iNK cells, potentially influencing human mucosal innate immunity during infection.