Cytotoxic granzyme C-expressing ILC1s contribute to antitumor immunity and neonatal autoimmunity Journal Article
| Authors: | Nixon, B. G.; Chou, C.; Krishna, C.; Dadi, S.; Michel, A. O.; Cornish, A. E.; Kansler, E. R.; Do, M. H.; Wang, X.; Capistrano, K. J.; Rudensky, A. Y.; Leslie, C. S.; Li, M. O. |
| Article Title: | Cytotoxic granzyme C-expressing ILC1s contribute to antitumor immunity and neonatal autoimmunity |
| Abstract: | Innate lymphocytes are integral components of the cellular immune system that can coordinate host defense against a multitude of challenges and trigger immunopathology when dysregulated. Natural killer (NK) cells and innate lymphoid cells (ILCs) are innate immune effectors postulated to functionally mirror conventional cytotoxic T lymphocytes and helper T cells, respectively. Here, we showed that the cytolytic molecule granzyme C was expressed in cells with the phenotype of type 1 ILCs (ILC1s) in mouse liver and salivary gland. Cell fate-mapping and transfer studies revealed that granzyme C-expressing innate lymphocytes could be derived from ILC progenitors and did not interconvert with NK cells, ILC2s, or ILC3s. Granzyme C defined a maturation state of ILC1s. These granzyme C-expressing ILC1s required the transcription factors T-bet and, to a lesser extent, Eomes and support from transforming growth factor-β (TGF-β) signaling for their maintenance in the salivary gland. In a transgenic mouse breast cancer model, depleting ILC1s caused accelerated tumor growth. ILC1s gained granzyme C expression following interleukin-15 (IL-15) stimulation, which enabled perforin-mediated cytotoxicity. Constitutive activation of STAT5, a transcription factor regulated by IL-15, in granzyme C-expressing ILC1s triggered lethal perforin-dependent autoimmunity in neonatal mice. Thus, granzyme C marks a cytotoxic effector state of ILC1s, broadening their function beyond "helper-like" lymphocytes. |
| Keywords: | mouse; animal; animals; mice; natural killer cell; killer cells, natural; perforin; autoimmunity; innate immunity; immunity, innate; interleukin 15; granzymes; interleukin-15; granzyme |
| Journal Title: | Science Immunology |
| Volume: | 7 |
| Issue: | 70 |
| ISSN: | 2470-9468 |
| Publisher: | Amer Assoc Advancement Science |
| Date Published: | 2022-04-01 |
| Start Page: | eabi8642 |
| Language: | English |
| DOI: | 10.1126/sciimmunol.abi8642 |
| PUBMED: | 35394814 |
| PROVIDER: | scopus |
| PMCID: | PMC9233921 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 May 2022 -- Source: Scopus |
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