A novel unconventional T cell population enriched in Crohn’s disease

Abstract

ObjectiveOne of the current hypotheses to explain the proinflammatory immune response in IBD is a dysregulated T cell reaction to yet unknown intestinal antigens. As such, it may be possible to identify disease-associated T cell clonotypes by analysing the peripheral and intestinal T-cell receptor (TCR) repertoire of patients with IBD and controls.DesignWe performed bulk TCR repertoire profiling of both the TCR alpha and beta chains using high-throughput sequencing in peripheral blood samples of a total of 244 patients with IBD and healthy controls as well as from matched blood and intestinal tissue of 59 patients with IBD and disease controls. We further characterised specific T cell clonotypes via single-cell RNAseq.ResultsWe identified a group of clonotypes, characterised by semi-invariant TCR alpha chains, to be significantly enriched in the blood of patients with Crohn’s disease (CD) and particularly expanded in the CD8+ T cell population. Single-cell RNAseq data showed an innate-like phenotype of these cells, with a comparable gene expression to unconventional T cells such as mucosal associated invariant T and natural killer T (NKT) cells, but with distinct TCRs.ConclusionsWe identified and characterised a subpopulation of unconventional Crohn-associated invariant T (CAIT) cells. Multiple evidence suggests these cells to be part of the NKT type II population. The potential implications of this population for CD or a subset thereof remain to be elucidated, and the immunophenotype and antigen reactivity of CAIT cells need further investigations in future studies.

Crohn’s-associated invariant T cells (CAITs) recognise small sulfonate molecules on CD1d

“…Only significant p values from a t-test with Holm method for multiple testing correction are shown (*<0.05, **<0.01, ***<0.001, ****<0.0001). (G.) Frequency of CAITlike NKT type II TCRs from Almeida et al (attached to a large cluster on figure 1A) and non-CAIT like NKT type II TCRs in Crohn’s disease and healthy cohorts from Rosati et al 1. Only significant p value (****<0.0001) from a Mann-Whitney U-test is shown.…”

“…To further investigate the possible role of NKT type II cells in CD, we searched all NKT type II sequences reported in Almeida et al in our previously published TCR data from patients with CD and healthy controls 1 3. Only TCRs from NKT type II cells with the characteristic CAIT TCRalpha chain motif showed significant enrichment in patients with CD, while other TCRs were found in comparable amounts in patients and controls (figure 1G).…”

Research progress on application of single-cell TCR/BCR sequencing technology to the tumor immune microenvironment, autoimmune diseases, and infectious diseases

“…The pattern and dynamics of these individual immune cells in liver fibrosis contribute to elucidating the protective mechanism of TCR in the chronic liver injury response ( 36 ). The TCRα chain is significantly enriched in the blood of patients with Crohn’s disease (CD), particularly in CD8+ T cell populations, whereas the potential effects of Crohn’s associated invariant T-cell subpopulations on CD remains to be elucidated ( 37 ). A total of 1650 glutamic acid decarboxylase 65-kilodalton isoform (GAD65)-specific CD4(+) T cells were isolated and 1003 different TCRs were identified in the peripheral blood of 6 patients and 10 patients with type 1 diabetes mellitus who were positive for islet autoantibodies.…”

GPR65, a novel regulator of helper T‐cell polarization in inflammatory bowel disease

“…Theory supports unknown intestinal antigens could lead to dysregulated proinflammatory T‐cell immune responses. 8 However, it is unclear whether interactions between innate and adaptive immune cells within the gut are through microbe‐associated molecular pattern (MAMP) ‐ pattern recognition receptor (PRR) interactions, processing of intestinal antigens through MHC class II, or both. Investigations have reported that toll‐like receptor and MHC class II pathways can support one another due to similar processing of ligands/antigens within endosomal cellular compartments.…”

“…Recognizing that GPR65 actions in epithelial cells, 6 macrophages, 7 and CD4 + T cells 5 contribute to the pathogenesis of IBD, this raises the question of whether innate immune cells regulate GPR65‐mediated T‐cell polarization towards proinflammatory T H 1 and T H 17 cells. Theory supports unknown intestinal antigens could lead to dysregulated proinflammatory T‐cell immune responses 8 . However, it is unclear whether interactions between innate and adaptive immune cells within the gut are through microbe‐associated molecular pattern (MAMP) ‐ pattern recognition receptor (PRR) interactions, processing of intestinal antigens through MHC class II, or both.…”