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Innate lymphoid cells (ILCs) including lymphoid tissue-inducer (LTi) cells, IL-22-producing NKp46+ innate cells and IL-13-producing nuocytes play important roles in regulating intestinal microbiota, defence against pathogens and formation of lymphoid tissue1-4. Their development is dependent on Id2 and Rorγt or Rorα5-7. Lineage tracing experiments have shown that the common lymphoid precursor gives rise to nuocytes, LTi cells and NKp46+ ILCs6,8,9, but these studies have not deciphered the discrete steps and transcription factors that specify ILC subset development, activation and maintenance. Whether NKp46+ ILCs arise directly from LTi cells, or rather represent a separate lineage that diverges earlier in development, remains controversial10-12. We investigated the requirement for the transcriptional master regulator T-bet (encoded by Tbx21) which is critical for the development of both T cells and NK cells13,14, in driving differentiation of ILC populations. Here we report that T-bet played an essential role for the development of NKp46+ ILCs, but was dispensable for LTi cells or nuocytes. Tbx21+/+ LTi cells adopted an NKp46+ phenotype in vitro and in vivo but not in the absence of Tbx21. Decrease of T-bet expression coordinately reduced Notch1 and Notch2 and we show Notch signaling is necessary for the transition of LTi cells into NKp46+ ILCs. In addition, Tbx21−/− mice have an accumulation in CD4− LTi cells and differentiation into NKp46+ ILCs came solely from this population. Our results pinpoint T-bet as the critical regulator of NKp46+ ILC differentiation by regulation of Notch2 signaling. NKp46+ cells are an important element of the protective intestinal mucosal cellular arsenal, and here, we uncover the distinct molecular pathways that guide the development of NKp46+ ILCs.

Ectopic lymphoid structures form in a wide range of inflammatory conditions, including infection, autoimmune disease, and cancer. In the context of infection, this response can be beneficial for the host: influenza A virus infection-induced pulmonary ectopic germinal centers give rise to more broadly cross-reactive antibody responses, thereby generating cross-strain protection. However, despite the ubiquity of ectopic lymphoid structures and their role in both health and disease, little is known about the mechanisms by which inflammation is able to convert a peripheral tissue into one that resembles a secondary lymphoid organ. Here, we show that type I IFN produced after viral infection can induce CXCL13 expression in a phenotypically distinct population of lung fibroblasts, driving CXCR5-dependent recruitment of B cells and initiating ectopic germinal center formation. This identifies type I IFN as a novel inducer of CXCL13, which, in combination with other stimuli, can promote lung remodeling, converting a nonlymphoid tissue into one permissive to functional tertiary lymphoid structure formation.

Denton et al. show that during influenza infection of mice, type I interferon can induce CXCL13 de novo in pulmonary PGDFRα+ fibroblasts. This chemokine drives CXCR5-dependent recruitment of B cells to the lung, thereby supporting pulmonary germinal center formation., Ectopic lymphoid structures form in a wide range of inflammatory conditions, including infection, autoimmune disease, and cancer. In the context of infection, this response can be beneficial for the host: influenza A virus infection–induced pulmonary ectopic germinal centers give rise to more broadly cross-reactive antibody responses, thereby generating cross-strain protection. However, despite the ubiquity of ectopic lymphoid structures and their role in both health and disease, little is known about the mechanisms by which inflammation is able to convert a peripheral tissue into one that resembles a secondary lymphoid organ. Here, we show that type I IFN produced after viral infection can induce CXCL13 expression in a phenotypically distinct population of lung fibroblasts, driving CXCR5-dependent recruitment of B cells and initiating ectopic germinal center formation. This identifies type I IFN as a novel inducer of CXCL13, which, in combination with other stimuli, can promote lung remodeling, converting a nonlymphoid tissue into one permissive to functional tertiary lymphoid structure formation., Graphical Abstract