A novel unconventional T cell population enriched in Crohn's disease
Language English Country Great Britain, England Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
35264446
PubMed Central
PMC9554086
DOI
10.1136/gutjnl-2021-325373
PII: gutjnl-2021-325373
Knihovny.cz E-resources
- Keywords
- Crohn's disease, IBD, T-cell receptor, alpha beta T cells, mucosal immunology,
- MeSH
- CD8-Positive T-Lymphocytes MeSH
- Crohn Disease * genetics MeSH
- Humans MeSH
- Natural Killer T-Cells * MeSH
- Receptors, Antigen, T-Cell, alpha-beta genetics MeSH
- Receptors, Antigen, T-Cell metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Receptors, Antigen, T-Cell, alpha-beta MeSH
- Receptors, Antigen, T-Cell MeSH
OBJECTIVE: One 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. DESIGN: We 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. RESULTS: We 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. CONCLUSIONS: We 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.
CEITEC Masaryk University Brno Czech Republic
Department of Dermatology University Hospital Schleswig Holstein Kiel Schleswig Holstein Germany
Department of Immunology St Jude Children's Research Hospital Memphis Tennessee USA
Dmitry Rogachev National Research Center of Pediatric Hematology Moscow Russian Federation
Institute of Epidemiology and Biobank POPGEN Christian Albrechts University of Kiel Kiel Germany
Institute of Immunology Christian Albrechts University of Kiel Kiel Schleswig Holstein Germany
Interdisciplinary Crohn Colitis Centre Minden Minden Germany
See more in PubMed
Kostic AD, Xavier RJ, Gevers D. The microbiome in inflammatory bowel disease: current status and the future ahead. Gastroenterology 2014;146:1489–99. 10.1053/j.gastro.2014.02.009 PubMed DOI PMC
Klag T, Stange EF, Wehkamp J. Defective antibacterial barrier in inflammatory bowel disease. Dig Dis 2013;31:310–6. 10.1159/000354858 PubMed DOI
Ciccarelli O, Barkhof F, Bodini B, et al. . Pathogenesis of multiple sclerosis: insights from molecular and metabolic imaging. Lancet Neurol 2014;13:807–22. 10.1016/S1474-4422(14)70101-2 PubMed DOI
Ilonen J, Lempainen J, Veijola R. The heterogeneous pathogenesis of type 1 diabetes mellitus. Nat Rev Endocrinol 2019;15:635–50. 10.1038/s41574-019-0254-y PubMed DOI
Ray K. Ibd: genotypes and phenotypes of IBD. Nat Rev Gastroenterol Hepatol 2015;12:672. 10.1038/nrgastro.2015.188 PubMed DOI
Kaser A, Zeissig S, Blumberg RS. Inflammatory bowel disease. Annu Rev Immunol 2010;28:573–621. 10.1146/annurev-immunol-030409-101225 PubMed DOI PMC
Imam T, Park S, Kaplan MH, et al. . Effector T helper cell subsets in inflammatory bowel diseases. Front Immunol 2018;9:1212. 10.3389/fimmu.2018.01212 PubMed DOI PMC
Rosati E, Dowds CM, Liaskou E, et al. . Overview of methodologies for T-cell receptor repertoire analysis. BMC Biotechnol 2017;17:61. 10.1186/s12896-017-0379-9 PubMed DOI PMC
Doorenspleet ME, Westera L, Peters CP, et al. . Profoundly Expanded T-cell Clones in the Inflamed and Uninflamed Intestine of Patients With Crohn’s Disease. Journal of Crohn's and Colitis 2017;11:831–9. 10.1093/ecco-jcc/jjx012 PubMed DOI
Wu J, Pendegraft AH, Byrne-Steele M, et al. . Expanded TCRβ CDR3 clonotypes distinguish Crohn's disease and ulcerative colitis patients. Mucosal Immunol 2018;11:1487–95. 10.1038/s41385-018-0046-z PubMed DOI
Chapman CG, Yamaguchi R, Tamura K, et al. . Characterization of T-cell receptor repertoire in inflamed tissues of patients with Crohn's disease through deep sequencing. Inflamm Bowel Dis 2016;22:1275–85. 10.1097/MIB.0000000000000752 PubMed DOI
Allez M, Auzolle C, Ngollo M, et al. . T cell clonal expansions in ileal Crohn's disease are associated with smoking behaviour and postoperative recurrence. Gut 2019;68:1961–70. 10.1136/gutjnl-2018-317878 PubMed DOI
Treiner E, Duban L, Bahram S, et al. . Selection of evolutionarily conserved mucosal-associated invariant T cells by MR1. Nature 2003;422:164–9. 10.1038/nature01433 PubMed DOI
Greenaway HY, Ng B, Price DA, et al. . NKT and MAIT invariant TCRα sequences can be produced efficiently by VJ gene recombination. Immunobiology 2013;218:213–24. 10.1016/j.imbio.2012.04.003 PubMed DOI
Godfrey DI, Uldrich AP, McCluskey J, et al. . The burgeoning family of unconventional T cells. Nat Immunol 2015;16:1114–23. 10.1038/ni.3298 PubMed DOI
Kaminski H, Couzi L, Eberl M. Unconventional T cells and kidney disease. Nat Rev Nephrol 2021;17:795–813. 10.1038/s41581-021-00466-8 PubMed DOI
Serriari N-E, Eoche M, Lamotte L, et al. . Innate mucosal-associated invariant T (MAIT) cells are activated in inflammatory bowel diseases. Clin Exp Immunol 2014;176:266–74. 10.1111/cei.12277 PubMed DOI PMC
Liao C-M, Zimmer MI, Wang C-R. The functions of type I and type II natural killer T cells in inflammatory bowel diseases. Inflamm Bowel Dis 2013;19:1330–8. 10.1097/MIB.0b013e318280b1e3 PubMed DOI PMC
Almeida CF, Smith DGM, Cheng T-Y, et al. . Benzofuran sulfonates and small self-lipid antigens activate type II NKT cells via CD1d. Proc Natl Acad Sci U S A 2021;118:e2104420118. 10.1073/pnas.2104420118 PubMed DOI PMC
Pogorelyy MV, Elhanati Y, Marcou Q, et al. . Persisting fetal clonotypes influence the structure and overlap of adult human T cell receptor repertoires. PLoS Comput Biol 2017;13:e1005572. 10.1371/journal.pcbi.1005572 PubMed DOI PMC
Hegazy AN, West NR, Stubbington MJT, et al. . Circulating and Tissue-Resident CD4+ T Cells With Reactivity to Intestinal Microbiota Are Abundant in Healthy Individuals and Function Is Altered During Inflammation. Gastroenterology 2017;153:1320–37. 10.1053/j.gastro.2017.07.047 PubMed DOI PMC
Rosati E, Pogorelyy MV, Dowds CM, et al. . Identification of disease-associated traits and Clonotypes in the T cell receptor repertoire of monozygotic twins affected by inflammatory bowel diseases. J Crohns Colitis 2020;14:778–90. 10.1093/ecco-jcc/jjz179 PubMed DOI PMC
Goyette P, Boucher G, Mallon D, et al. . High-Density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis. Nat Genet 2015;47:172–9. 10.1038/ng.3176 PubMed DOI PMC
Goyette P, Boucher G, Mallon D, et al. . High-Density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis. Nat Genet 2015;47:172–9. 10.1038/ng.3176 PubMed DOI PMC
Degenhardt F, Wendorff M, Wittig M, et al. . Construction and benchmarking of a multi-ethnic reference panel for the imputation of HLA class I and II alleles. Hum Mol Genet 2019;28:2078–92. 10.1093/hmg/ddy443 PubMed DOI PMC
Degenhardt F, Mayr G, Wendorff M, et al. . Transethnic analysis of the human leukocyte antigen region for ulcerative colitis reveals not only shared but also ethnicity-specific disease associations. Hum Mol Genet 2021;30:356–69. 10.1093/hmg/ddab017 PubMed DOI PMC
Butler A, Hoffman P, Smibert P, et al. . Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat Biotechnol 2018;36:411–20. 10.1038/nbt.4096 PubMed DOI PMC
Godfrey DI, Koay H-F, McCluskey J, et al. . The biology and functional importance of MAIT cells. Nat Immunol 2019;20:1110–28. 10.1038/s41590-019-0444-8 PubMed DOI
De Biasi S, Gibellini L, Lo Tartaro D, et al. . Circulating mucosal-associated invariant T cells identify patients responding to anti-PD-1 therapy. Nat Commun 2021;12:1669. 10.1038/s41467-021-21928-4 PubMed DOI PMC
Zhao J, Zhang S, Liu Y, et al. . Single-Cell RNA sequencing reveals the heterogeneity of liver-resident immune cells in human. Cell Discov 2020;6:22. 10.1038/s41421-020-0157-z PubMed DOI PMC
Park D, Kim HG, Kim M, et al. . Differences in the molecular signatures of mucosal-associated invariant T cells and conventional T cells. Sci Rep 2019;9:7094. 10.1038/s41598-019-43578-9 PubMed DOI PMC
Lepore M, Kalinichenko A, Kalinicenko A, et al. . Parallel T-cell cloning and deep sequencing of human MAIT cells reveal stable oligoclonal TCRβ repertoire. Nat Commun 2014;5:3866. 10.1038/ncomms4866 PubMed DOI
Lepore M, Lewinsohn DA, Lewinsohn DM. T cell receptor diversity, specificity and promiscuity of functionally heterogeneous human MR1-restricted T cells. Mol Immunol 2021;130:64–8. 10.1016/j.molimm.2020.12.009 PubMed DOI PMC
Park H-J, Shin MS, Kim M, et al. . Transcriptomic analysis of human IL-7 receptor alpha low and high effector memory CD8+ T cells reveals an age-associated signature linked to influenza vaccine response in older adults. Aging Cell 2019;18:e12960. 10.1111/acel.12960 PubMed DOI PMC
Pereira BI, De Maeyer RPH, Covre LP, et al. . Sestrins induce natural killer function in senescent-like CD8+ T cells. Nat Immunol 2020;21:684–94. 10.1038/s41590-020-0643-3 PubMed DOI PMC
Van Rhijn I, Young DC, Im JS, et al. . Cd1D-Restricted T cell activation by nonlipidic small molecules. Proc Natl Acad Sci U S A 2004;101:13578–83. 10.1073/pnas.0402838101 PubMed DOI PMC
Oh SF, Praveena T, Song H, et al. . Host immunomodulatory lipids created by symbionts from dietary amino acids. Nature 2021;600:302–7. 10.1038/s41586-021-04083-0 PubMed DOI PMC
Shugay M, Britanova OV, Merzlyak EM, et al. . Towards error-free profiling of immune repertoires. Nat Methods 2014;11:653–5. 10.1038/nmeth.2960 PubMed DOI
Bolotin DA, Poslavsky S, Mitrophanov I, et al. . MiXCR: software for comprehensive adaptive immunity profiling. Nat Methods 2015;12:380–1. 10.1038/nmeth.3364 PubMed DOI
Benjamini Y, Hochberg Y. Royal statistical Society. 57. Wiley, 1995: 289–300.
Csardi Gabor NT. The igraph software package for complex network research. InterJournal, Complex Systems 2006;5:1–9.
Gowthaman R, Pierce BG. TCRmodel: high resolution modeling of T cell receptors from sequence. Nucleic Acids Res 2018;46:W396–401. 10.1093/nar/gky432 PubMed DOI PMC
Zheng X, Shen J, Cox C, et al. . HIBAG--HLA genotype imputation with attribute bagging. Pharmacogenomics J 2014;14:192–200. 10.1038/tpj.2013.18 PubMed DOI PMC
Harvey RF, Bradshaw JM. A simple index of crohn’s-disease activity. The Lancet 1980;315:514. 10.1016/S0140-6736(80)92767-1 PubMed DOI
Waniek S, di Giuseppe R, Plachta-Danielzik S, et al. . Association of vitamin E levels with metabolic syndrome, and MRI-Derived body fat volumes and liver fat content. Nutrients 2017;9:1143. 10.3390/nu9101143 PubMed DOI PMC
Koch M, Borggrefe J, Barbaresko J, et al. . Dietary patterns associated with magnetic resonance imaging-determined liver fat content in a general population study. Am J Clin Nutr 2014;99:369–77. 10.3945/ajcn.113.070219 PubMed DOI PMC
Nöthlings U, Krawczak M. [PopGen. A population-based biobank with prospective follow-up of a control group]. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2012;55:831–5. 10.1007/s00103-012-1487-2 PubMed DOI
Korsunsky I, Millard N, Fan J, et al. . Fast, sensitive and accurate integration of single-cell data with harmony. Nat Methods 2019;16:1289–96. 10.1038/s41592-019-0619-0 PubMed DOI PMC
Finak G, McDavid A, Yajima M, et al. . Mast: a flexible statistical framework for assessing transcriptional changes and characterizing heterogeneity in single-cell RNA sequencing data. Genome Biol 2015;16:278. 10.1186/s13059-015-0844-5 PubMed DOI PMC
Repertoire-based mapping and time-tracking of T helper cell subsets in scRNA-Seq
Targeted depletion of TRBV9+ T cells as immunotherapy in a patient with ankylosing spondylitis
