Innate Lymphoid Cells Integrate Sensing and Plasticity to Control Fungal Infections [ILC Sequencing]

Innate lymphoid cells (ILCs) are crucial regulators of tissue immunity, yet their role in antifungal defense remains incompletely understood. Through our findings, we demonstrate that pulmonary ILCs can sense fungal pathogens by recognizing fungal cell wall components via pattern recognition receptors, leading to the activation and type-1 polarization in vitro. Mechanistically, we identify Syk/Akt-dependent signaling as one of the key drivers of ILC activation upon fungal encounters. Aspergillus fumigatus infection reshapes this response in vivo, where elevated TGF-ß and IL-1ß levels facilitate a shift from type-1 ILC activity to IL-17A release. Ultimately, IL-17-producing ILCs are crucial in resolving the infection and restoring normal tissue homeostasis. Moreover, adoptive transfer models in lymphocyte-deficient Rag2-/-?c-/- mice reveal that ILCs restrain excessive inflammation while hindering fungal clearance, highlighting their dual role in regulating antifungal immunity. Remarkably, ILCs lacking the non-receptor tyrosine kinase Tec disrupts caspase-8 activation, leading to enhanced proliferation of type-1 ILCs. Consequently, improved fungal clearance enhances host survival by strengthening antifungal immunity. Our findings uncover hitherto unrecognized roles of ILCs as fungal sensors and early modulators of antifungal immunity. Therefore, targeting Tec kinase signaling in ILCs holds great promise as a therapeutic option to enhance antifungal immunity, especially in patients at risk for invasive A. fumigatus infections. Overall design: Smart-Seq2 (bulk RNAseq) analysis of sorted CD90+lin- pulmonary ILC subsets derived from Aspergillus fumigatus (ATCC204305) infected mice (3*10^7 spores/mouse) or corresponding controls. ILCs of isolated mice were compared to control mice (mock infected, saline). Each sample corresponds to pooled biological replicates (n=3-4/sample); Cells were then stained for CD45 expression, lineage markers to exclude T cells, B cells, myeloid cells, erythroid cells and conventional NK cells (anti-CD49b [DX5], -CD5, -CD3e, -TCRß, -CD45R [B220], -CD19, -CD11b, -CD11c, -Gr-1 [Ly-6G/C], -7-4, -Ter-119; all from Miltenyi Biotech), CD90/Thy1 (anti-CD90) and viability (Zombie Dye Violet, Biolegend)