Eric Vivier, Marco De Giovanni, Alexei V. Tumanov, Antonio Pires da Silva Baptista, Jason G. Cyster, Paula S. Norris, Carl De Trez, Gérard Eberl, Carl F. Ware, Yvan Saeys, Robin Browaeys, James P. Di Santo, Bart N. Lambrecht, Matthias Vanderkerken, Satoshi Fukuyama, Hamida Hammad, Charlotte L. Scott, VIB-UGent Center for Inflammation Research [Gand, Belgique] (IRC), VIB [Belgium], Universiteit Gent = Ghent University (UGENT), University of California [San Francisco] (UC San Francisco), University of California (UC), The University of Tokyo (UTokyo), Sanford Burnham Prebys Medical Discovery Institute, Microenvironnement et Immunité - Microenvironment and Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunité Innée - Innate Immunity, Innate Pharma, Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Texas Health Science Center, The University of Texas Health Science Center at Houston (UTHealth), Vrije Universiteit Brussel (VUB), Erasmus University Medical Center [Rotterdam] (Erasmus MC), M. Vanderkerken is supported by a fellowship from Fonds Wetenschappelijk Onderzoek Vlaanderen, A.P. Baptista is supported by a Marie-Sklodowska Curie Action fellowship as part of Horizon 2020, C.L. Scott is supported by the Fonds Wetenschappelijk Onderzoek Vlaanderen and a European Research Council starting grant, Y. Saeys is supported by the Fonds Wetenschappelijk Onderzoek Vlaanderen and the Marylou Ingram Scholar program, H. Hammad is supported by a research initiative grant from Ghent University, A.V. Tumanov is supported by grants from the National Institutes of Health (AI135574) and the Max and Minnie Tomerlin Voelcker Fund, and B.N. Lambrecht is supported by a European Research Council advanced grant, a research initiative grant from Ghent University, and an Excellence of Science research grant., Universiteit Gent = Ghent University [Belgium] (UGENT), University of California [San Francisco] (UCSF), University of California, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Pulmonary Medicine, HUGOT, Bérengère, Department of Bio-engineering Sciences, and Cellular and Molecular Immunology
Conventional dendritic cells (cDCs) bridge antigen detection to the induction of adaptive immunity, playing crucial roles in host defense. Vanderkerken, Baptista, et al. show that LTα1β2-expressing ILC3s, together with B cells, control the size of the splenic cDC compartment and cDC2 differentiation., The spleen contains a myriad of conventional dendritic cell (cDC) subsets that protect against systemic pathogen dissemination by bridging antigen detection to the induction of adaptive immunity. How cDC subsets differentiate in the splenic environment is poorly understood. Here, we report that LTα1β2-expressing Rorgt+ ILC3s, together with B cells, control the splenic cDC niche size and the terminal differentiation of Sirpα+CD4+Esam+ cDC2s, independently of the microbiota and of bone marrow pre-cDC output. Whereas the size of the splenic cDC niche depended on lymphotoxin signaling only during a restricted time frame, the homeostasis of Sirpα+CD4+Esam+ cDC2s required continuous lymphotoxin input. This latter property made Sirpα+CD4+Esam+ cDC2s uniquely susceptible to pharmacological interventions with LTβR agonists and antagonists and to ILC reconstitution strategies. Together, our findings demonstrate that LTα1β2-expressing Rorgt+ ILC3s drive splenic cDC differentiation and highlight the critical role of ILC3s as perpetual regulators of lymphoid tissue homeostasis.