HIC1 links retinoic acid signalling to group 3 innate lymphoid cell-dependent regulation of intestinal immunity and homeostasis
Bibliographic record
Abstract
Abstract The intestinal immune system must be able to respond to a wide variety of infectious organisms while maintaining tolerance to non-pathogenic microbes and food antigens. The Vitamin A metabolite retinoic acid (RA) has been implicated in the regulation of this balance, partially by regulating innate lymphoid cell (ILC) responses in the intestine. However, the molecular mechanisms of RA-dependent intestinal immunity and homeostasis remain elusive. Here we define a role for the transcriptional repressor Hypermethylated in cancer 1 (HIC1, ZBTB29) in the regulation of ILC responses in the intestine. Intestinal ILCs express HIC1 in a vitamin A-dependent manner. In the absence of HIC1, group 3 ILCs (ILC3s) are lost, resulting in increased susceptibility to infection with the bacterial pathogen Citrobacter rodentium . In addition, the loss of ILC3s leads to a local and systemic increase in IFN-γ-producing T cells that prevents the development of protective immunity against infection with the parasitic helminth Trichuris muris . Thus, RA-dependent expression of HIC1 in ILC3s regulates intestinal homeostasis and protective immunity. Author Summary Innate lymphoid cells (ILCs) are emerging as important regulators of immune responses at barrier sites such as the intestine. However, the molecular mechanisms that control this are not well described. In the intestine, the Vitamin A metabolite retinoic acid (RA) has been shown to be an important component of the homeostatic mechanisms. In this manuscript, we show that the RA-dependent transcription factor Hypermethylated in cancer 1 (HIC1, ZBTB29) is required for ILC homeostasis and function in the steady state as well as following infection with the bacterial pathogen Citrobacter rodentium or the helminth parasite Trichuris muris . Thus, HIC1 links RA signalling to intestinal immune responses. Further, our results identify HIC1 as a potential target to modulate ILC responses in vivo in health and disease.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".