Metabolic control of T cell immune response through glycans in inflammatory bowel disease

Abstract

Mucosal T lymphocytes from patients with ulcerative colitis (UC) were previously shown to display a deficiency in branched N-glycosylation associated with disease severity. However, whether this glycosylation pathway shapes the course of the T cell response constituting a targeted-specific mechanism in UC remains largely unknown. In this study, we demonstrated that metabolic supplementation of ex vivo mucosal T cells from patients with active UC with -acetylglucosamine (GlcNAc) resulted in enhancement of branched N-glycosylation in the T cell receptor (TCR), leading to suppression of T cell growth, inhibition of the T helper 1 (Th1)/Th17 immune response, and controlled T cell activity. We further demonstrated that mouse models displaying a deficiency in the branched N-glycosylation pathway (, ) exhibited increased susceptibility to severe forms of colitis and early-onset disease. Importantly, the treatment of these mice with GlcNAc reduced disease severity and suppressed disease progression due to a controlled T cell-mediated immune response at the intestinal mucosa. In conclusion, our human ex vivo and preclinical results demonstrate the targeted-specific immunomodulatory properties of this simple glycan, proposing a therapeutic approach for patients with UC.

Protein Glycosylation as a Diagnostic and Prognostic Marker of Chronic Inflammatory Gastrointestinal and Liver Diseases

“…Glycans regulate T-cell development, activation, signaling, differentiation, and proliferation, as well as thymocyte selection. 8,27,[29][30][31] Alterations in these processes can lead to autoimmune diseases and cancer. 5,32 It is not clear whether alterations in cell glycosylation profiles occur as an early event (inducing) or late event (accelerating) in intestinal inflammation.…”

“…5,32 It is not clear whether alterations in cell glycosylation profiles occur as an early event (inducing) or late event (accelerating) in intestinal inflammation. Intestinal T cells from patients with IBD have glycome profiles that differ from those individuals without IBD, characterized by decreased levels of branched N-glycans 19,30 and increased levels of core fucosylation (the addition of a fucose residue to the core structure of N-linked glycans with an a1,6 linkage). 33 These changes increase Tcell-mediated intestinal immune response.…”

“…T cells from inflamed colonic mucosa of patients with active UC have reduced expression of the a-1,6mannosylglycoprotein 6-b-N-acetylglucosaminyltransferase gene (MGAT5) or overexpression of the fucosyltransferase 8 gene (FUT8), 30,33 compared with cells from patients without UC. T cells from patients with IBD have a glycome profile that has been associated with a decreased threshold for activation and increased signaling and inflammatory response 30,33 (Figure 1). However, it is not clear whether changes in the glycoprofile of T cells are a cause or a consequence of intestinal inflammation.…”

“…During colitis induction with dextran sodium sulfate (DSS), mice with the disruption of MGAT5 gene develop more severe colitis, with earlier onset, than mice without disruption of this gene, with increased responses of T-helper (Th)1 and Th17 cells. 30 Alternatively, FUT8 knockout mice develop a less-severe colitis than mice that express wild-type FUT8, producing lower levels of Th1 and Th2 cytokines. 33 Mice that express human fucosyltransferase 2 (FUT2) from a transgene have defects in T-cell development and develop spontaneous colitis.…”

Human T cell glycosylation and implications on immune therapy for cancer

“…26,122 In inflammatory bowel disease, metabolic supplementation of mucosal T cells with GlcNAc leads to enhancement of N-glycosylation branching on the TCR, thereby controlling the T cell immune response ( Table 3). 114 In an alternative metabolic glycoengineering approach, monosaccharide analogs are used to introduce non-natural chemical moieties (such as ketones, azides, alkynes, thiols, …) in glycans, enabling bioorthogonal conjugation of small molecules such as toxins, drugs, imaging agents and polymers via click chemistry. Using this bioorthogonal click chemistry, a library of more than 60 different cell lines was generated with different sialic acid modifications, leading to dramatic increases in binding with Siglec family members.…”