Interleukin-23 Induces CTLA-4 Expression on Group 3 Innate Lymphoid Cells to Regulate Intestinal Inflammation

Core Concepts

Interleukin-23 induces the expression of the immunoregulatory checkpoint molecule CTLA-4 on group 3 innate lymphoid cells (ILC3s), which is essential for restraining the pathological outcomes of IL-23 and maintaining intestinal homeostasis.

Abstract

The content explores the mechanisms by which interleukin-23 (IL-23), a major mediator and therapeutic target in chronic inflammatory diseases, can elicit both beneficial and pathological outcomes in the intestine. Through single-cell RNA sequencing, the authors identified that IL-23 receptor-expressing cells in the intestine are predominantly T cells and group 3 innate lymphoid cells (ILC3s). Surprisingly, the authors found that IL-23 induces a potent upregulation of the immunoregulatory checkpoint molecule cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) on ILC3s. This CTLA-4 upregulation is 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. The authors further demonstrated that IL-23-induced CTLA-4+ ILC3s are necessary and sufficient to reduce co-stimulatory molecules and increase PD-L1 bioavailability on intestinal myeloid cells, thereby regulating the inflammatory response. Importantly, human ILC3s also upregulated CTLA-4 in response to IL-23 or gut inflammation, and this correlated with immunoregulation in inflammatory bowel disease. These findings reveal that ILC3-intrinsic CTLA-4 is an essential checkpoint that restrains the pathological outcomes of IL-23, suggesting that disruption of these regulatory lymphocytes, which occurs in inflammatory bowel disease, contributes to chronic inflammation.

Stats

Mice lacking CTLA-4 on ILC3s exhibited reduced regulatory T cells and elevated inflammatory T cells. Mice lacking CTLA-4 on ILC3s had more severe intestinal inflammation. Human ILC3s upregulated CTLA-4 in response to IL-23 or gut inflammation, and this correlated with immunoregulation in inflammatory bowel disease.

Quotes

"Unexpectedly, we identified potent upregulation of the immunoregulatory checkpoint molecule cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) on ILC3s." "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." "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 disease, contributes to chronic inflammation."

Key Insights Distilled From

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

by Anees Ahmed,... at www.nature.com 06-12-2024

https://www.nature.com/articles/s41586-024-07537-3

Deeper Inquiries

How do the regulatory mechanisms involving CTLA-4-expressing ILC3s differ in other inflammatory conditions beyond inflammatory bowel disease?

In other inflammatory conditions beyond inflammatory bowel disease, the regulatory mechanisms involving CTLA-4-expressing ILC3s may vary based on the specific context of the disease. While the study highlights the role of CTLA-4 on ILC3s in restraining interleukin-23-mediated inflammation in the intestine, the response of these cells in different inflammatory conditions could be influenced by various factors such as the tissue microenvironment, the type of immune cells involved, and the specific cytokine milieu present. For instance, in autoimmune diseases like rheumatoid arthritis or psoriasis, where IL-23 signaling is also implicated, CTLA-4-expressing ILC3s may interact with different immune cell populations and exhibit distinct regulatory functions compared to their role in the intestine. Understanding these context-specific differences in the regulatory mechanisms of CTLA-4-expressing ILC3s across various inflammatory conditions is crucial for developing targeted therapies tailored to each disease setting.

What are the potential therapeutic implications of targeting the CTLA-4 pathway on ILC3s for the treatment of chronic inflammatory diseases?

Targeting the CTLA-4 pathway on ILC3s holds significant therapeutic implications for the treatment of chronic inflammatory diseases. The study suggests that CTLA-4-expressing ILC3s play a crucial role in restraining IL-23-mediated inflammation in the intestine by promoting immunoregulation and dampening inflammatory responses. Therefore, modulating the CTLA-4 pathway on ILC3s could serve as a promising therapeutic strategy to mitigate chronic inflammation in conditions where IL-23 signaling is dysregulated. By enhancing the regulatory capacity of ILC3s through CTLA-4 activation, it may be possible to restore immune homeostasis and limit tissue damage associated with chronic inflammatory diseases. Furthermore, targeting the CTLA-4 pathway on ILC3s could offer a more precise and localized approach to immune modulation, potentially reducing the risk of systemic side effects commonly seen with broad immunosuppressive therapies.

What other immune checkpoint molecules or regulatory pathways might be involved in shaping the beneficial versus pathological outcomes of IL-23 signaling in the intestine?

In addition to CTLA-4, several other immune checkpoint molecules and regulatory pathways may be involved in shaping the beneficial versus pathological outcomes of IL-23 signaling in the intestine. One such molecule is programmed cell death protein 1 (PD-1), which, similar to CTLA-4, acts as a negative regulator of immune responses and is known to modulate T cell activation and tolerance. The PD-1/PD-L1 pathway, along with other immune checkpoints like TIM-3, LAG-3, and VISTA, could interact with IL-23 signaling to fine-tune the balance between pro-inflammatory and regulatory responses in the intestine. Moreover, regulatory pathways such as the TGF-β signaling pathway, which is critical for maintaining immune tolerance and tissue homeostasis, may also intersect with IL-23-mediated inflammation to influence the overall immune response. Understanding the crosstalk between these immune checkpoint molecules and regulatory pathways in the context of IL-23 signaling is essential for unraveling the complex mechanisms that govern intestinal inflammation and for identifying novel therapeutic targets for chronic inflammatory diseases.