Cytotoxic granzyme C-expressing ILC1s contribute to antitumor immunity and neonatal autoimmunity

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-beta (TGF-beta) 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.

Automated summary

Innate lymphocytes are important components of the cellular immune system. They can defend the host against various challenges and can lead to immunopathology when dysregulated. This study found that granzyme C, a cytolytic molecule, was expressed in a specific type of innate lymphoid cells (ILC1s) in the liver and salivary gland of mice. These granzyme C-expressing ILC1s were derived from ILC progenitors and did not convert into NK cells, ILC2s, or ILC3s. Granzyme C marked a maturation state of ILC1s, and its expression in ILC1s required specific transcription factors and support from transforming growth factor-beta signaling. Depleting ILC1s in a mouse breast cancer model resulted in accelerated tumor growth. IL-15 stimulation induced granzyme C expression in ILC1s, enabling them to exhibit perforin-mediated cytotoxicity. However, constitutive activation of STAT5 in granzyme C-expressing ILC1s led to lethal perforin-dependent autoimmunity in neonatal mice. This study broadens the understanding of the function of ILC1s beyond helper-like lymphocytes.