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Autocrine vitamin D signaling switches off pro-inflammatory programs of T_H1 cells.

ABSTRACT: The molecular mechanisms governing orderly shutdown and retraction of CD4⁺ type 1 helper T (T_H1) cell responses remain poorly understood. Here we show that complement triggers contraction of T_H1 responses by inducing intrinsic expression of the vitamin D (VitD) receptor and the VitD-activating enzyme CYP27B1, permitting T cells to both activate and respond to VitD. VitD then initiated the transition from pro-inflammatory interferon-γ⁺ T_H1 cells to suppressive interleukin-10⁺ cells. This process was primed by dynamic changes in the epigenetic landscape of CD4⁺ T cells, generating super-enhancers and recruiting several transcription factors, notably c-JUN, STAT3 and BACH2, which together with VitD receptor shaped the transcriptional response to VitD. Accordingly, VitD did not induce interleukin-10 expression in cells with dysfunctional BACH2 or STAT3. Bronchoalveolar lavage fluid CD4⁺ T cells of patients with COVID-19 were T_H1-skewed and showed de-repression of genes downregulated by VitD, from either lack of substrate (VitD deficiency) and/or abnormal regulation of this system.

SUBMITTER: Chauss D

PROVIDER: S-EPMC7612139 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Autocrine vitamin D signaling switches off pro-inflammatory programs of TH1 cells.

Chauss Daniel D Freiwald Tilo T McGregor Reuben R Yan Bingyu B Wang Luopin L Nova-Lamperti Estefania E Kumar Dhaneshwar D Zhang Zonghao Z Teague Heather H West Erin E EE Vannella Kevin M KM Ramos-Benitez Marcos J MJ Bibby Jack J Kelly Audrey A Malik Amna A Freeman Alexandra F AF Schwartz Daniella M DM Portilla Didier D Chertow Daniel S DS John Susan S Lavender Paul P Kemper Claudia C Lombardi Giovanna G Mehta Nehal N NN Cooper Nichola N Lionakis Michail S MS Laurence Arian A Kazemian Majid M Afzali Behdad B

Nature immunology 20211111 1

The molecular mechanisms governing orderly shutdown and retraction of CD4+ type 1 helper T (TH1) cell responses remain poorly understood. Here we show that complement triggers contraction of TH1 responses by inducing intrinsic expression of the vitamin D (VitD) receptor and the VitD-activating enzyme CYP27B1, permitting T cells to both activate and respond to VitD. VitD then initiated the transition from pro-inflammatory interferon-γ+ TH1 ce ...[more]

PMID: 34764490

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Project description:Infants affected by Hirschsprung disease (HSCR), a neurodevelopmental congenital disorder, lack ganglia of the intrinsic enteric nervous system (aganglionosis) in a variable length of the colon, and are prone to developing severe Hirschsprung-associated enterocolitis (HAEC). HSCR patients typically show abnormal dense innervation of extrinsic cholinergic nerve fibers throughout the aganglionic rectosigmoid. Cholinergic signaling has been reported to reduce inflammatory response. Consequently, a sparse extrinsic cholinergic innervation in the mucosa of the rectosigmoid correlates with increased inflammatory immune cell frequencies and higher incidence of HAEC in HSCR patients. However, whether cholinergic signals influence the pro-inflammatory immune response of intestinal epithelial cells (IEC) is unknown. Here, we analyzed colonic IEC isolated from 43 HSCR patients with either a low or high mucosal cholinergic innervation density (fiber-low versus fiber-high) as well as from control tissue. Compared to fiber-high samples, IEC purified from fiber-low rectosigmoid expressed significantly higher levels of IL-8 but not TNF-α, IL-10, TGF-β1, Muc-2 or tight junction proteins. IEC from fiber-low rectosigmoid showed higher IL-8 protein concentrations in cell lysates as well as prominent IL-8 immunoreactivity compared to IEC from fiber-high tissue. Using the human colonic IEC cell line SW480 we demonstrated that cholinergic signals suppress lipopolysaccharide-induced IL-8 secretion via the alpha 7 nicotinic acetylcholine receptor (a7nAChR). In conclusion, we showed for the first time that the presence of a dense mucosal cholinergic innervation is associated with decreased secretion of IEC-derived pro-inflammatory IL-8 in the rectosigmoid of HSCR patients likely dependent on a7nAChR activation. Owing to the association between IL-8 and enterocolitis-prone, fiber-low HSCR patients, targeted therapies against IL-8 might be a promising immunotherapy candidate for HAEC treatment.

Project description:Hirschsprung disease (HSCR) is a rare congenital anomaly characterized by the absence of enteric ganglia in the distal intestinal tract. While classified as a multigenic disorder, the altered function of the RET tyrosine kinase receptor is responsible for the majority of the pathogenesis of HSCR. Recent evidence demonstrate a strong association between RET and the homeostasis of immune system. Here, we utilize a unique cohort of fifty HSCR patients to fully characterize the expression of RET receptor on both innate (monocytes and Natural Killer lymphocytes) and adaptive (B and T lymphocytes) human peripheral blood mononuclear cells (PBMCs) and to explore the role of RET signaling in the immune system. We show that the increased expression of RET receptor on immune cell subsets from HSCR individuals correlates with the presence of loss-of-function RET mutations. Moreover, we demonstrate that the engagement of RET on PBMCs induces the modulation of several inflammatory genes. In particular, RET stimulation with glial-cell line derived neurotrophic factor family (GDNF) and glycosyl-phosphatidylinositol membrane anchored co-receptor ?1 (GFR?1) trigger the up-modulation of genes encoding either for chemokines (CCL20, CCL2, CCL3, CCL4, CCL7, CXCL1) and cytokines (IL-1?, IL-6 and IL-8) and the down-regulation of chemokine/cytokine receptors (CCR2 and IL8-R?). Although at different levels, the modulation of these "RET-dependent genes" occurs in both healthy donors and HSCR patients. We also describe another set of genes that, independently from RET stimulation, are differently regulated in healthy donors versus HSCR patients. Among these "RET-independent genes", there are CSF-1R, IL1-R1, IL1-R2 and TGF?-1, whose levels of transcripts were lower in HSCR patients compared to healthy donors, thus suggesting aberrancies of inflammatory responses at mucosal level. Overall our results demonstrate that immune system actively participates in the physiopathology of HSCR disease by modulating inflammatory programs that are either dependent or independent from RET signaling.

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Autocrine vitamin D signaling switches off pro-inflammatory programs of T_H1 cells.

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Autocrine vitamin D signaling switches off pro-inflammatory programs of T<sub>H</sub>1 cells.

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Autocrine vitamin D signaling switches off pro-inflammatory programs of TH1 cells.

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Autocrine vitamin D signaling switches off pro-inflammatory programs of T&lt;sub&gt;H&lt;/sub&gt;1 cells.

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Autocrine vitamin D signaling switches off pro-inflammatory programs of T_H1 cells.

Autocrine vitamin D signaling switches off pro-inflammatory programs of T<sub>H</sub>1 cells.