IL-33 Promotes Egress of Group 2 Innate Lymphoids Cells (ILC2) from the Bone Marrow

Rationale:  Group 2 innate lymphocytes (ILC2) are mucosally embedded effector cells that promote type 2 immune responses to allergens, viruses, and other environmental insults.  In peripheral tissues, ILC2 robustly proliferate and express cytokines in response to the alarmin IL-33.  However, the role of IL-33 on ILC2 development and egress from the bone marrow remains unclear.  

Methods:  We assessed the frequencies and functional capacities of ILC2 in the bone marrow, lung, skin, and mesenteric lymph nodes of WT, IL-33-deficient, and/or ST2-deficient mice by flow cytometry.  

Results:  We identified that deficiency in IL-33 signaling lead to an accumulation of ILC2 in the bone marrow and a decrease in ILC2 in the lungs, skin, and mesenteric lymph nodes compared to wild type mice.  These bone marrow and peripheral tissue ILC2 frequencies were established by an ILC2 cell-intrinsic mechanism.  Absent IL-33 signaling did not appreciably affect the capacity of bone marrow ILC2 to proliferate or secrete canonical ILC2-associated cytokines.  However, lack of IL-33 signaling significantly altered the chemokine receptor profile on bone marrow ILC2, with ST2-deficient ILC2 overexpressing Cx3cr1, Ccr7, Ccr9, Cxcr4, and Ptgdr2 compared to wild type ILC2.  Treatment of wild type ILC2 with IL-33 ex vivodecreased the expression of CXCR4, a major chemotactic signal for the retention of cells in the bone marrow.  Moreover, pharmacologic blockade of CXCR4 induced mobilization of ILC2 from the bone marrow of ST2-deficient mice.  

Conclusions: These data suggest a mechanism by which IL-33 negatively regulates CXCR4 expression on developing ILC2 leading to efficient egress of these cells from the bone marrow.