Abstract
Leukocyte Immunoglobulin-like Receptor B4 (LILRB4) null mice have an exacerbated T helper cell type 2 (Th2) immune response and pulmonary inflammation compared with Lilrb4+/+ animals when sensitized intranasally with ovalbumin (OVA) and low-dose lipopolysaccharide (LPS) followed by challenge with OVA. Moreover, OVA-challenged Lilrb4 −/− mice exhibit greater migration of antigen (Ag)-bearing dendritic cells (DCs) to lymph nodes and accumulation of interleukin 4- and interleukin 5-producing lymph node lymphocytes. The main objective of this study was to determine how the absence of LILRB4 leads to a greater number of DCs in the lymph nodes of Ag-challenged mice and increased lung Th2 inflammation. Mice were sensitized intranasally with PBS alone or containing OVA and LPS; additional cohorts were subsequently challenged with OVA. Expression of chemokine (C-C motif) ligand 21 (CCL21) in the lung was assessed immunohistologically. OVA ingestion and expression of LILRB4 and chemokine (C-C motif) receptor 7 (CCR7) were quantified by flow cytometry. Inhalation of OVA and LPS induced upregulation of LILRB4 selectively on lung Ag-bearing DCs. After sensitization and challenge, the lung lymphatic vessels of Lilrb4 −/− mice expressed more CCL21, a chemokine that directs the migration of DCs from peripheral tissue to draining lymph nodes, compared with Lilrb4+/+ mice. In addition, lung DCs of challenged Lilrb4 −/− mice expressed more CCR7, the CCL21 receptor. The lungs of challenged Lilrb4 −/− mice also contained significantly greater numbers of CD4+ cells expressing interleukin-4 or interleukin-5, consistent with the greater number of Ag-bearing DCs and Th2 cells in lymph nodes and the attendant exacerbated Th2 lung pathology. Our data establish a new mechanism by which LILRB4 can downregulate the development of pathologic allergic inflammation: reduced upregulation of key molecules needed for DC migration leading to decreases in Th2 cells in lymph nodes and their target tissue.
Highlights
Dendritic cells (DCs) are among the earliest participants in the initiation of both protective and pathologic adaptive immunity and inflammation
We show that expression of CCL21 on lung lymphatic vessels and CCR7 on OVA+ lung DCs is increased after challenge of OVA/LPS-sensitized Lilrb4+/+ and Lilrb42/2 mice, but the increases are significantly greater in the Lilrb42/2 strain
In mice treated with PBS, Leukocyte Immunoglobulin-like Receptor B4 (LILRB4) was expressed on 55% of DCs with a mean fluorescence intensity (MFI) of 273, whereas in mice given OVA and LPS, 84% of DCs were LILRB4+ with an MFI of 1012 (Figs. 1C and 1D)
Summary
Dendritic cells (DCs) are among the earliest participants in the initiation of both protective and pathologic adaptive immunity and inflammation. In response to danger signals such as lipopolysaccharide (LPS), immature tissue DCs undergo an innate immune maturation process so as to degrade endocytosed antigen (Ag) and present peptides in association with highly expressed cell surface major histocompatibility molecules in concert with upregulated costimulatory molecules. This leads to expansion of Ag-specific effector T cells in tissue-draining lymph nodes (LNs), a hallmark of adaptive immunity [1]. Whereas much is known about the innate immune signals that initiate this process through the migration of Ag-bearing DCs to LNs, less is understood about control mechanisms that inhibit DC migration and the subsequent development of pathologic adaptive immune inflammation
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