Stepwise Chromatin and Transcriptional Acquisition of an Intraepithelial Lymphocyte Program

Overview

Journal Nat Immunol

Date 2021 Mar 9

PMID 33686285

Citations 21

Authors

Mariya London

Angelina M Bilate

Tiago B R Castro

Tomohisa Sujino

Daniel Mucida

Affiliations

Soon will be listed here.

Abstract

Mesenteric lymph node (mLN) T cells undergo tissue adaptation upon migrating to intestinal lamina propria and epithelium, ensuring appropriate balance between tolerance and resistance. By combining mouse genetics with single-cell and chromatin analyses, we uncovered the molecular imprinting of gut epithelium on T cells. Transcriptionally, conventional and regulatory (T) CD4 T cells from mLN, lamina propria and intestinal epithelium segregate based on the gut layer they occupy; trajectory analysis suggests a stepwise loss of CD4 programming and acquisition of an intraepithelial profile. T cell fate mapping coupled with RNA sequencing and assay for transposase-accessible chromatin followed by sequencing revealed that the T cell program shuts down before an intraepithelial program becomes fully accessible at the epithelium. Ablation of CD4-lineage-defining transcription factor ThPOK results in premature acquisition of an intraepithelial lymphocyte profile by mLN T cells, partially recapitulating epithelium imprinting. Thus, coordinated replacement of the circulating lymphocyte program with site-specific transcriptional and chromatin changes is necessary for tissue imprinting.

Citing Articles

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References

Mucida D, Kutchukhidze N, Erazo A, Russo M, Lafaille J, Curotto de Lafaille M . Oral tolerance in the absence of naturally occurring Tregs. J Clin Invest. 2005; 115(7):1923-33. PMC: 1142115. DOI: 10.1172/JCI24487. View

Bilate A, Lafaille J . Induced CD4+Foxp3+ regulatory T cells in immune tolerance. Annu Rev Immunol. 2012; 30:733-58. DOI: 10.1146/annurev-immunol-020711-075043. View

Furusawa Y, Obata Y, Fukuda S, Endo T, Nakato G, Takahashi D . Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature. 2013; 504(7480):446-50. DOI: 10.1038/nature12721. View

Hadis U, Wahl B, Schulz O, Hardtke-Wolenski M, Schippers A, Wagner N . Intestinal tolerance requires gut homing and expansion of FoxP3+ regulatory T cells in the lamina propria. Immunity. 2011; 34(2):237-46. DOI: 10.1016/j.immuni.2011.01.016. View

Sujino T, London M, Hoytema van Konijnenburg D, Rendon T, Buch T, Silva H . Tissue adaptation of regulatory and intraepithelial CD4⁺ T cells controls gut inflammation. Science. 2016; 352(6293):1581-6. PMC: 4968079. DOI: 10.1126/science.aaf3892. View

Atarashi K, Tanoue T, Shima T, Imaoka A, Kuwahara T, Momose Y . Induction of colonic regulatory T cells by indigenous Clostridium species. Science. 2011; 331(6015):337-41. PMC: 3969237. DOI: 10.1126/science.1198469. View

Atarashi K, Tanoue T, Oshima K, Suda W, Nagano Y, Nishikawa H . Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature. 2013; 500(7461):232-6. DOI: 10.1038/nature12331. View

Olivares-Villagomez D, Van Kaer L . Intestinal Intraepithelial Lymphocytes: Sentinels of the Mucosal Barrier. Trends Immunol. 2017; 39(4):264-275. PMC: 8056148. DOI: 10.1016/j.it.2017.11.003. View

McDonald B, Jabri B, Bendelac A . Diverse developmental pathways of intestinal intraepithelial lymphocytes. Nat Rev Immunol. 2018; 18(8):514-525. PMC: 6063796. DOI: 10.1038/s41577-018-0013-7. View

10.

Vantourout P, Hayday A . Six-of-the-best: unique contributions of γδ T cells to immunology. Nat Rev Immunol. 2013; 13(2):88-100. PMC: 3951794. DOI: 10.1038/nri3384. View

11.

Reis B, Rogoz A, Costa-Pinto F, Taniuchi I, Mucida D . Mutual expression of the transcription factors Runx3 and ThPOK regulates intestinal CD4⁺ T cell immunity. Nat Immunol. 2013; 14(3):271-80. PMC: 3804366. DOI: 10.1038/ni.2518. View

12.

Reis B, Hoytema van Konijnenburg D, Grivennikov S, Mucida D . Transcription factor T-bet regulates intraepithelial lymphocyte functional maturation. Immunity. 2014; 41(2):244-56. PMC: 4287410. DOI: 10.1016/j.immuni.2014.06.017. View

13.

Konkel J, Maruyama T, Carpenter A, Xiong Y, Zamarron B, Hall B . Control of the development of CD8αα+ intestinal intraepithelial lymphocytes by TGF-β. Nat Immunol. 2011; 12(4):312-9. PMC: 3062738. DOI: 10.1038/ni.1997. View

14.

Bilate A, Bousbaine D, Mesin L, Agudelo M, Leube J, Kratzert A . Tissue-specific emergence of regulatory and intraepithelial T cells from a clonal T cell precursor. Sci Immunol. 2017; 1(2):eaaf7471. PMC: 6296461. DOI: 10.1126/sciimmunol.aaf7471. View

15.

Mucida D, Husain M, Muroi S, van Wijk F, Shinnakasu R, Naoe Y . Transcriptional reprogramming of mature CD4⁺ helper T cells generates distinct MHC class II-restricted cytotoxic T lymphocytes. Nat Immunol. 2013; 14(3):281-9. PMC: 3581083. DOI: 10.1038/ni.2523. View

16.

Rubtsov Y, Niec R, Josefowicz S, Li L, Darce J, Mathis D . Stability of the regulatory T cell lineage in vivo. Science. 2010; 329(5999):1667-71. PMC: 4262151. DOI: 10.1126/science.1191996. View

17.

Setoguchi R, Tachibana M, Naoe Y, Muroi S, Akiyama K, Tezuka C . Repression of the transcription factor Th-POK by Runx complexes in cytotoxic T cell development. Science. 2008; 319(5864):822-5. DOI: 10.1126/science.1151844. View

18.

Zemmour D, Zilionis R, Kiner E, Klein A, Mathis D, Benoist C . Single-cell gene expression reveals a landscape of regulatory T cell phenotypes shaped by the TCR. Nat Immunol. 2018; 19(3):291-301. PMC: 6069633. DOI: 10.1038/s41590-018-0051-0. View

19.

Miragaia R, Gomes T, Chomka A, Jardine L, Riedel A, Hegazy A . Single-Cell Transcriptomics of Regulatory T Cells Reveals Trajectories of Tissue Adaptation. Immunity. 2019; 50(2):493-504.e7. PMC: 6382439. DOI: 10.1016/j.immuni.2019.01.001. View

20.

Bilate A, London M, Castro T, Mesin L, Bortolatto J, Kongthong S . T Cell Receptor Is Required for Differentiation, but Not Maintenance, of Intestinal CD4 Intraepithelial Lymphocytes. Immunity. 2020; 53(5):1001-1014.e20. PMC: 7677182. DOI: 10.1016/j.immuni.2020.09.003. View