ILC3s control splenic cDC homeostasis via lymphotoxin signaling

Matthias Vanderkerken (1, 2) , Antonio P. Baptista (1, 2) , Marco de Giovanni (3) , Satoshi Fukuyama (4) , Robin Browaeys (1, 2) , Charlotte L. Scott (1, 2) , Paula S. Norris (5) , Gerard Eberl (6) , James P. Di Santo (7) , Eric Vivier (8, 9) , Yvan Saeys (1, 2) , Hamida Hammad (1, 2) , Jason G. Cyster (3) , Carl F. Ware (5) , Alexei V. Tumanov (10) , Carl de Trez (11) , Bart N. Lambrecht (1, 2, 12)

1 IRC - VIB-UGent Center for Inflammation Research [Gand, Belgique]
2 UGENT - Universiteit Gent = Ghent University [Belgium]
3 UC San Francisco - University of California [San Francisco]
4 UTokyo - The University of Tokyo
5 Sanford Burnham Prebys Medical Discovery Institute
6 Microenvironnement et Immunité - Microenvironment and Immunity
7 Immunité Innée - Innate Immunity
8 Innate Pharma
9 CIML - Centre d'Immunologie de Marseille - Luminy
10 University of Texas Health Science Center
11 VUB - Vrije Universiteit Brussel
12 Erasmus MC - Erasmus University Medical Center [Rotterdam]

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 LTα 1 β 2-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 LTα 1 β 2-expressing Rorgt + ILC3s drive splenic cDC differentiation and highlight the critical role of ILC3s as perpetual regulators of lymphoid tissue homeostasis.

Domains: Life Sciences [q-bio]; Immunology

Matthias Vanderkerken, Antonio P. Baptista, Marco de Giovanni, Satoshi Fukuyama, Robin Browaeys, et al.. ILC3s control splenic cDC homeostasis via lymphotoxin signaling. Journal of Experimental Medicine, 2021, 218 (5), pp.e20190835. ⟨10.1084/jem.20190835⟩. ⟨pasteur-03258252⟩