RORγt+ Innate Lymphoid Cells Acquire a Proinflammatory Program upon Engagement of the Activating Receptor NKp44

• IL-22 expression is confined to NKp44+ RORγt+ ILCs
• NKp44 engagement selectively induces a proinflammatory program in RORγt+ ILCs
• Engagement of NKp44 and cytokine receptors results in a strong synergistic effect
• RORγt+ ILCs are activated by NKp44 ligands expressed on tumor epithelial cells

SummaryRORγt+ innate lymphoid cells (ILCs) are crucial players of innate immune responses and represent a major source of interleukin-22 (IL-22), which has an important role in mucosal homeostasis. The signals required by RORγt+ ILCs to express IL-22 and other cytokines have been elucidated only partially. Here we showed that RORγt+ ILCs can directly sense the environment by the engagement of the activating receptor NKp44. NKp44 triggering in RORγt+ ILCs selectively activated a coordinated proinflammatory program, including tumor necrosis factor (TNF), whereas cytokine stimulation preferentially induced IL-22 expression. However, combined engagement of NKp44 and cytokine receptors resulted in a strong synergistic effect. These data support the concept that NKp44+ RORγt+ ILCs can be activated without cytokines and are able to switch between IL-22 or TNF production, depending on the triggering stimulus.

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