SLAM-family receptors promote resolution of ILC2-mediated inflammation

Yuande Wang, Yuhe Quan, Junming He, Shasha Chen () and Zhongjun Dong ()
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Yuande Wang: the First Affiliated Hospital of Anhui Medical University and Institute of Clinical Immunology, Anhui Medical University
Yuhe Quan: Tsinghua University
Junming He: Tsinghua University
Shasha Chen: the First Affiliated Hospital of Anhui Medical University and Institute of Clinical Immunology, Anhui Medical University
Zhongjun Dong: the First Affiliated Hospital of Anhui Medical University and Institute of Clinical Immunology, Anhui Medical University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Type 2 innate lymphoid cells (ILC2) initiate early allergic inflammation in the lung, but the factors that promote subsequent resolution of type 2 inflammation and prevent prolonged ILC2 activation are not fully known. Here we show that SLAM-family receptors (SFR) play essential roles in this process. We demonstrate dynamic expression of several SFRs on ILC2s during papain-induced type 2 immunity in mice. SFR deficiency exacerbates ILC2-driven eosinophil infiltration in the lung, and results in a significant increase in IL-13 production by ILC2s exclusively in mediastinal lymph nodes (MLN), leading to increased dendritic cell (DC) and TH2 cell numbers. In MLNs, we observe more frequent interaction between ILC2s and bystander T cells, with T cell-expressed SFRs (especially SLAMF3 and SLAMF5) acting as self-ligands to suppress IL-13 production by ILC2s. Mechanistically, homotypic engagement of SFRs at the interface between ILC2s and T cells delivers inhibitory signaling primarily mediated by SHIP-1. This prevents activation of NF-κB, driven by IL-7 and IL-33, two major drivers of ILC2-mediated type 2 immunity. Thus, our study shows that an ILC2-DC-TH2 regulatory axis may promote the resolution of pulmonary type 2 immune responses, and highlights SLAMF3/SLAMF5 as potential therapeutic targets for ameliorating type 2 immunity.

Date: 2024
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DOI: 10.1038/s41467-024-49466-9

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