CTLA-4-expressing ILC3s restrain interleukin-23-mediated inflammation

Anees Ahmed, Ann M. Joseph, Jordan Zhou, Veronika Horn, Jazib Uddin, Mengze Lyu, Jeremy Goc, Robbyn E. Sockolow, James B. Wing, Eric Vivier, Shimon Sakaguchi and Gregory F. Sonnenberg ()
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Anees Ahmed: Cornell University
Ann M. Joseph: Cornell University
Jordan Zhou: Cornell University
Veronika Horn: Cornell University
Jazib Uddin: Cornell University
Mengze Lyu: Cornell University
Jeremy Goc: Cornell University
Robbyn E. Sockolow: Cornell University
James B. Wing: Osaka University
Eric Vivier: Innate Pharma
Shimon Sakaguchi: Osaka University
Gregory F. Sonnenberg: Cornell University

Nature, 2024, vol. 630, issue 8018, 976-983

Abstract: Abstract Interleukin (IL-)23 is a major mediator and therapeutic target in chronic inflammatory diseases that also elicits tissue protection in the intestine at homeostasis or following acute infection1–4. However, the mechanisms that shape these beneficial versus pathological outcomes remain poorly understood. To address this gap in knowledge, we performed single-cell RNA sequencing on all IL-23 receptor-expressing cells in the intestine and their acute response to IL-23, revealing a dominance of T cells and group 3 innate lymphoid cells (ILC3s). Unexpectedly, we identified potent upregulation of the immunoregulatory checkpoint molecule cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) on ILC3s. This pathway was activated by gut microbes and IL-23 in a FOXO1- and STAT3-dependent manner. Mice lacking CTLA-4 on ILC3s exhibited reduced regulatory T cells, elevated inflammatory T cells and more-severe intestinal inflammation. IL-23 induction of CTLA-4+ ILC3s was necessary and sufficient to reduce co-stimulatory molecules and increase PD-L1 bioavailability on intestinal myeloid cells. Finally, human ILC3s upregulated CTLA-4 in response to IL-23 or gut inflammation and correlated with immunoregulation in inflammatory bowel disease. These results reveal ILC3-intrinsic CTLA-4 as an essential checkpoint that restrains the pathological outcomes of IL-23, suggesting that disruption of these lymphocytes, which occurs in inflammatory bowel disease5–7, contributes to chronic inflammation.

Date: 2024
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DOI: 10.1038/s41586-024-07537-3

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