Allergen inhalation transforms the lungs into a permissive environment for local IgE responses

Abstract

Abstract Immunoglobulin E (IgE) is the primary cause of allergic diseases and must be tightly regulated. Production of IgE occurs when activated B cells undergo class switch recombination (CSR) to IgE. These key events are rare, thus questions on which B cell subsets undergo IgE CSR, where IgE CSR predominantly occurs, and which molecular and cellular signals promote IgE CSR remain unresolved. We modeled allergic asthma by intranasal administration of ragweed pollen and ovalbumin (OVA) in mice, and found that allergen inhalation induced the formation of lymphoid aggregates and production of OVA-specific IgE in the lungs. Using fluorescent mice reporting IgE switching, we revealed that allergen-sensitized lungs were a major site of IgE CSR with IgG1 +memory B cells (MBCs) being the dominant IgE-switching cells. Single-cell transcriptomics and flow cytometry analyses revealed a tight correlation between CCR6 expression and lung IgG1 +MBCs, potentially explaining their recruitment/retention in the respiratory mucosa. Furthermore, lungMBCs underwent IgE CSR more frequentlythan MBCs in the draining lymph nodes or spleen. Since IgE CSR requires interleukin 4 (IL-4), we used IL-4 reporter mice and found that IL-4-producing T H2 cells were enriched in the lungs compared with lymphoid organs. Co-culture experiments using purified lung MBCs from IgE reporter mice with lung or splenic effector CD4 +T cells revealed that IgE CSR was elevated in the presence of lungT cells, suggesting lung-infiltrating T H2 cells drive elevated IgE CSR in the lungs. This study clarifies that the respiratory mucosa is a key site of IgE CSR – in allergic asthma the lung environment supports IgE CSR with IgG1 +MBCs and CD4 +T cells collaborating to promote local IgE responses. Supported by grants from NIH (F31 HL156459, T32 AI007508, R01 HL165120, R21 AI159456)