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

Citation

Verified title: CTLA-4-expressing ILC3s restrain interleukin-23-mediated inflammation
Publication year: 2024
DOI: 10.1038/s41586-024-07537-3
Metadata source: crossref-doi (confidence: high)
Original local title: CTLA-4-expressing ILC3s restrain interleukin-23-mediated inflammation

Ingest Mode

Mode: focused manual crystallization mode
Meaning: this source page was manually upgraded and now supports source-linked ILC3 restraint-mechanism claims.
Durable synthesis status: selected high-confidence extrapulmonary ILC3 checkpoint claims from this source were propagated into ILC3 entity and mechanism pages with explicit gut-context labeling.

Source Type

primary intestinal ILC3 checkpoint-regulation study
Evidence profile: scRNA-seq of IL-23R-positive cells, IL-23 stimulation, ILC3-specific CTLA-4 perturbation, myeloid-cell checkpoint readouts, Treg/inflammatory-T-cell outcomes, and human ILC3 validation in gut inflammation
Knowledge note status: focused source note suitable for extrapulmonary mechanism context, not for direct lung-disease claims

Evidence Profile

Overall confidence: high for source-specific claims that IL-23 and gut microbes induce a CTLA-4-positive regulatory ILC3 branch that restrains intestinal inflammation.
Evidence tags: #cell/ILC3 #topic/regulation #axis/IL23 #axis/checkpoint_restraint #tissue/gut #species/human #species/mouse #status/focused_crystallization
Primary biological axis: IL-23 does not only activate inflammatory ILC3 outputs; it can also induce an ILC3-intrinsic CTLA-4 checkpoint program that restrains pathological inflammation.

Why It Matters Here

This source gives the ILC3 wiki a much-needed restraint branch. Even though it is gut-centered, it is valuable because many ILC3 pages otherwise read as mostly activation biology; this paper shows that IL-23 biology in ILC3s also includes an endogenous checkpoint program that shapes inflammatory outcomes.

Key Findings

IL-23-responsive intestinal cells were dominated by T cells and ILC3s, and acute IL-23 exposure strongly induced CTLA-4 on ILC3s in this source.
Gut microbes and IL-23 induced the CTLA-4-positive ILC3 program through FOXO1- and STAT3-dependent signaling.
Mice lacking CTLA-4 on ILC3s had fewer regulatory T cells, more inflammatory T cells, and more severe intestinal inflammation.
CTLA-4-positive ILC3s altered myeloid-cell costimulatory and inhibitory-ligand balance in ways that restrained pathological inflammation in the reported system.
Human ILC3s also upregulated CTLA-4 in response to IL-23 or gut inflammation, supporting translational relevance within mucosal disease.

Claim-Level Confidence

High confidence: this source supports an ILC3-intrinsic CTLA-4 checkpoint branch that restrains IL-23-mediated intestinal inflammation.
High confidence: IL-23 can induce both inflammatory and restraining ILC3 programs, and this paper directly supports the restraint side of that balance.
Medium-high confidence: human ILC3 data support conservation of the CTLA-4 response in mucosal inflammation.
Low confidence: this source should not be rewritten as direct proof of a lung ILC3 CTLA-4 program without matched pulmonary evidence.

Methods and Context

Species/context: mouse intestine and human inflammatory bowel disease-related mucosal ILC3 biology.
Assay directness: strong for checkpoint mechanism and inflammatory restraint, but extrapulmonary relative to the lung wiki's main focus.
Best wiki use: extrapulmonary conserved mechanism candidate, ILC3 restraint logic, and IL-23 pathway complexity.

Caveats

This is a gut-centered source and must stay explicitly labeled as such.
It is best used to shape mechanistic hypotheses, not to claim direct pulmonary disease behavior.
Myeloid and Treg consequences should remain context-specific to the reported mucosal system.

Contradiction and Supersession

Contradiction status: this source balances activation-heavy IL-23/IL-17 ILC3 literature by adding a checkpoint-restraint branch.
Supersession status: not superseded; it is currently one of the clearest sources for an ILC3-intrinsic restraint program.