Bactericidal/permeability-increasing protein instructs dendritic cells to elicit Th22 cell response.

Neutrophil-derived bactericidal/permeability-increasing protein (BPI) is known for its bactericidal activity against gram-negative bacteria and neutralization of lipopolysaccharide. Here, we define BPI as a potent activator of murine dendritic cells (DCs). As shown in GM-CSF-cultured, bone-marrow-derived cells (BMDCs), BPI induces a distinct stimulation profile including IL-2, IL-6, and tumor necrosis factor expression. Conventional DCs also respond to BPI, while M-CSF-cultivated or peritoneal lavage macrophages do not. Subsequent to BPI stimulation of BMDCs, CD4⁺ T cells predominantly secrete IL-22 and, when naive, preferentially differentiate into T helper 22 (Th22) cells. Congruent with the tissue-protective properties of IL-22 and along with impaired IL-22 induction, disease severity is significantly increased during dextran sodium sulfate-induced colitis in BPI-deficient mice. Importantly, physiological diversification of intestinal microbiota fosters BPI-dependent IL-22 induction in CD4⁺ T cells derived from mesenteric lymph nodes. In conclusion, BPI is a potent activator of DCs and consecutive Th22 cell differentiation with substantial relevance in intestinal homeostasis. [Display omitted] • Bactericidal/permeability-increasing protein (BPI) is an activator of dendritic cells (DCs) • BPI-dependent DC activation mediates differentiation of naive CD4⁺ T cells into Th22 cells • Bpi ^−/− mice exhibit reduced IL-22 induction and increased disease severity during colitis • Microbiota diversification fosters BPI-dependent activation of IL-22-positive CD4⁺ T cells Bülow et al. show that bactericidal/permeability-increasing protein (BPI) has substantial relevance in intestinal homeostasis. Following activation of murine dendritic cells by BPI, CD4⁺ T cells predominantly differentiate into IL-22-secreting Th22 cells. This BPI-DC-IL-22 axis is fostered by diversification of intestinal microbiota and improves the outcome of dextran sodium sulfate-induced colitis. [ABSTRACT FROM AUTHOR]