Impaired Butyrate Induced Regulation of T Cell Surface Expression of CTLA-4 in Patients with Ulcerative Colitis.

Maria K Magnusson,Henric K Olsson,Lujain Maasfeh,Rajneesh Malhotra,Lena Öhman,Stefan Isaksson,Alexander Vidal

doi:10.3390/ijms22063084

Abstract

Patients with ulcerative colitis (UC) have reduced intestinal levels of short-chain fatty acids (SCFAs), including butyrate, which are important regulators of host–microbiota crosstalk. The aim was therefore to determine effects of butyrate on blood and intestinal T cells from patients with active UC. T cells from UC patients and healthy subjects were polyclonally stimulated together with SCFAs and proliferation, activation, cytokine secretion, and surface expression of cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) were analyzed. Butyrate induced comparable, dose dependent inhibition of activation and proliferation in blood T cells and activation in intestinal T cells from UC patients and healthy subjects. However, surface expression of the inhibitory molecule CTLA-4 on stimulated blood and intestinal T cells was impaired in UC patients and was not restored following butyrate treatment. Furthermore, unlike intestinal T cells from healthy subjects, butyrate was unable to downregulate secretion of interferon gamma (IFNγ), interleukin (IL)-4, IL-17A, and IL-10 in UC patients. Although seemingly normal inhibitory effects on T cell activation and proliferation, butyrate has an impaired ability to reduce cytokine secretion and induce surface expression of CTLA-4 in T cells from UC patients with active disease. Overall, these observations indicate a dysfunction in butyrate induced immune regulation linked to CTLA-4 signaling in T cells from UC patients during a flare.

Highlights

Introduction published maps and institutional affilInflammatory bowel disease (IBD), mainly comprising ulcerative colitis (UC) andCrohn’s disease (CD), is a chronic intestinal disorder ascribed to an exaggerated and protracted immune activity directed against the commensal microbiota which eventually results in inflammation of the intestine [1,2]
The effects of short chain fatty acids (SCFAs) on CD4+ and CD8+ T cell proliferation and activation were first analyzed in blood cells from healthy subjects (Figure 1a)
The current study demonstrates that butyrate inhibits activation and proliferation of blood and intestinal T cells obtained from UC patients and healthy subjects, butyrate does not downregulate cytokine secretion of intestinal T cells recovered from UC patients

Summary

Introduction

Crohn’s disease (CD), is a chronic intestinal disorder ascribed to an exaggerated and protracted immune activity directed against the commensal microbiota which eventually results in inflammation of the intestine [1,2]. The pathophysiology of the disease is incompletely understood but involves genetic, environmental and microbial factors. In UC, the inflammation involves the superficial mucosal layer, it extends proximally from rectum into the colon in a continuous fashion and affected individuals experience diarrhea, rectal bleeding, and abdominal pain [2]. Malfunctions in innate immunity seem to pave the way for inflammation, a key role for dysregulated T cell responses in propagation and perpetuation of the consequent inflammation in the gut is widely accepted [3]. The host-microbiota interplay is a crucial regulatory factor, training the immune system to differentiate the commensal bacteria from pathogens and iations

Objectives

Methods

Results

Conclusion