Leukocyte Ig-like Receptor B4 (LILRB4) Downregulates Key Steps in the Migration of Antigen-bearing Lung Dendritic Cells to Lymph Nodes in Th2 Inflammation (173.30)

Abstract

Abstract We previously reported that Lilrb4-/- mice have exacerbated Th2 immune responses and pulmonary inflammation compared with Lilrb4+/+ animals when sensitized with OVA and low-dose LPS followed by challenge with OVA. In addition, LILRB4 is selectively upregulated on Ag-bearing dendritic cells (DCs) in the lung and draining lymph nodes (LNs). Ag-challenged Lilrb4-/- mice exhibit increased migration of Ag-bearing DCs to LNs and accumulation of IL-4- and IL-5-producing LN lymphocytes. To determine how the absence of LILRB4 leads to more DCs in the LNs of Ag-challenged mice, animals were sensitized intranasally with PBS alone or OVA/LPS and were challenged with OVA. Four hours later, lungs were evaluated by immunohistology, and lung mononuclear cells were isolated for flow cytometry. The lung lymphatic vessels of Lilrb4-/- mice expressed significantly more CCL21, a chemokine that directs the migration of DCs to draining LNs. In addition, lung DCs of Lilrb4-/- mice expressed more CCR7, the CCL21 receptor. The lungs of Lilrb4-/- mice also contained significantly greater numbers of CD4+ cells expressing IL-4 or IL-5, consistent with the greater number of Ag-bearing DCs and Th2 cells in LNs and the attendant exacerbated Th2 lung pathology. Our data reveal that LILRB4 downregulates expression of two fundamental molecules that induce the migration of Ag-bearing DCs to LNs, thereby decreasing Th2 cell accumulation in LNs and lung and the ensuing pathologic pulmonary inflammation.