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

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.

Holothuria leucospilota polysaccharides (HLP) ameliorate colitis rats via regulation of the metabolic profiling and TLR4/NLRP3 signaling pathways

“…Propionic acid reduces inflammation by inhibiting the expression of chemokines and cytokines and regulating the activation of neutrophils (Chang et al., 2014). Butyrate is an important energy source for intestinal epithelial cells, which has the ability to regulate the growth of epithelial cells and immune response and repair intestinal mucosal injury (Magnusson et al., 2021). The results of MPEA analysis showed that HLP had a significant regulatory effect on propanoate metabolism and butanoate metabolism pathway ( p < .05).…”

Identification of hub genes and immune infiltration in ulcerative colitis using bioinformatics

“…Currently, the level of CTLA4 expression in UC remains unclear. Wang et al 58 and Magnusson et al 59 suggested that CTLA4 expression in T cells was lower in UC patients than in healthy individuals. However, other studies have shown that CTLA4 mRNA expression was significantly higher in colonic mucosal tissue from patients with active UC compared with controls devoid of inflammation 60 .…”

Identification of Potential Immune Checkpoint Inhibitor Targets in Gliomas via Bioinformatic Analyses

“…The immune checkpoint genes evaluated included CD274, also known as PD-L1, that encodes an immune inhibitory ligand expressed by hematopoietic and nonhematopoietic cells such as T cells and various tumor cells [ 39 ]. CTLA4, a member of the immunoglobulin superfamily, encodes a protein that transmits an inhibitory signal to T cells [ 40 ]. HAVCR2 or TIM3 is a cell surface marker expressed on CD8+ Th1 and CD4+ Th1 cells [ 41 ].…”