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

Autor: Ahmed, Anees, Joseph, Ann M., Zhou, Jordan, Horn, Veronika, Uddin, Jazib, Lyu, Mengze, Goc, Jeremy, JRI Live Cell Bank, Artis, David, Longman, Randy, Sonnenberg, Gregory F., Scherl, Ellen, Sockolow, Robbyn, Lukin, Dana, Jacob, Vinita, Sahyoun, Laura, Mintz, Michael, Gogokhia, Lasha, Ciecierega, Thomas, Solomon, Aliza
Zdroj: Nature; Jun2024, Vol. 630 Issue 8018, p976-983, 8p
Abstrakt: 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.Subsets of ILC3s upregulate the immunoregulatory checkpoint molecule CTLA-4 after stimulation in a microbiota-dependent manner, and advances to support CTLA-4+ ILC3s may represent a treatment opportunity in IL-23-driven chronic inflammation. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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