Segmented filamentous bacteria-induced epithelial MHCII regulates cognate CD4+ IELs and epithelial turnover

Tomáš Brabec; Martin Schwarzer; Katarína Kováčová; Martina Dobešová; Dagmar Schierová; Jiří Březina; Iva Pacáková; Dagmar Šrůtková; Osher Ben-Nun; Yael Goldfarb; Iva Šplíchalová; Michal Kolář; Jakub Abramson; Dominik Filipp; Jan Dobeš

doi:10.1084/jem.20230194

Segmented filamentous bacteria-induced epithelial MHCII regulates cognate CD4+ IELs and epithelial turnover

Tomáš Brabec, Martin Schwarzer, Katarína Kováčová, Martina Dobešová, Dagmar Schierová, Jiří Březina, Iva Pacáková, Dagmar Šrůtková, Osher Ben-Nun, Yael Goldfarb, Iva Šplíchalová, Michal Kolář, Jakub Abramson, Dominik Filipp, Jan Dobeš

Department of Immunology and Regenerative Biology

Research output: Contribution to journal › Article › peer-review

7 Citations (Scopus)

Abstract

Intestinal epithelial cells have the capacity to upregulate MHCII molecules in response to certain epithelial-adhesive microbes, such as segmented filamentous bacteria (SFB). However, the mechanism regulating MHCII expression as well as the impact of epithelial MHCII-mediated antigen presentation on T cell responses targeting those microbes remains elusive. Here, we identify the cellular network that regulates MHCII expression on the intestinal epithelium in response to SFB. Since MHCII on the intestinal epithelium is dispensable for SFB-induced Th17 response, we explored other CD4+ T cell-based responses induced by SFB. We found that SFB drive the conversion of cognate CD4+ T cells to granzyme+ CD8α+ intraepithelial lymphocytes. These cells accumulate in small intestinal intraepithelial space in response to SFB. Yet, their accumulation is abrogated by the ablation of MHCII on the intestinal epithelium. Finally, we show that this mechanism is indispensable for the SFB-driven increase in the turnover of epithelial cells in the ileum. This study identifies a previously uncharacterized immune response to SFB, which is dependent on the epithelial MHCII function.

Original language	English
Article number	e20230194
Number of pages	26
Journal	Journal of Experimental Medicine
Volume	221
Issue number	1
DOIs	https://doi.org/10.1084/jem.20230194
Publication status	Published - 1 Jan 2024

Bibliographical note

We are thankful to Martina Krausová and Šárka Kocourková from the Genomics and Bioinformatics core facility of the Institute of Molecular Genetics in Prague, Czech Republic, for the preparation of single-cell libraries and to Zdeněk Cimburek from the Flow Cytometry Core Facility of the Institute of Molecular Genetics in Prague, Czech Republic for suggestions related to cell sorting. We thank the Animal Facility in Krč personnel of the Institute of Molecular Genetics in Prague, Czech Republic for their excellent maintenance of our animal colonies and Šárka Maisnerová from the Laboratory of Gnotobiology, Institute of Microbiology in Nový Hrádek, Czech Republic for the GF and SFB-negative mice maintenance. We are thankful to Bernard Malissen (Centre d’Immunologie de Marseille Luminy, Marseille, France), Ulrich Kalinke (Helmholtz Centre for Infection Research, Hannover, Germany), and Veronika Sexl (Veterinary University of Vienna, Vienna, Austria) for valuable mouse strains.

Research in the Dobeš laboratory (J. Dobeš, T. Brabec, K. Kováčová, M. Dobešová, I. Pacáková) is kindly supported by the Czech Science Foundation JUNIOR STAR grant (no. 21-22435M), Czech Science Foundation grant (no. 22-30879S) and by Charles University PRIMUS grant (no. Primus/21/MED/003). M. Schwarzer and D. Šrůtková are supported by the Czech Science Foundation JUNIOR STAR grant (no. 21-19640M). D. Filipp, I. Šplichalová, and J. Březina are supported by grant no. 20-30350S and 22-30879S from the Czech Science Foundation. M. Kolář is supported by the Operational Programme Research, Development and Education project (no. CZ.02.1.01/0.0/0.0/16_019/0000785).

Author contributions: T. Brabec, D. Filipp, J. Abramson, and J. Dobeš initiated the project. T. Brabec and J. Dobeš designed the vast majority of experiments, critically discussed the data, and wrote and revised the manuscript in close collaboration. T. Brabec executed and analyzed the majority of the experiments, J. Dobeš executed some of the experiments and acquired the funding. J. Abramson and D. Filipp critically discussed the results, revised the manuscript, and contributed with critically important reagents. M. Schwarzer critically contributed to the design of gnotobiotic experiments and together with D. Šrůtková provided SFB monoisolates, performed all SFB colonization experiments and handled all gnotobiotic animals. K. Kováčová performed majority of microscopy analysis and provided technical support for the project. M. Dobešová performed some of the experiments, carried out the majority of mouse genotyping, and provided technical support for the project. J. Březina performed animal irradiation, critically discussed the data and the manuscript. I. Pacáková provided support in some of the experiments. D. Schierová, O. Ben-Nun, Y. Goldfarb, and I. Šplichalová performed some of the experiments. M. Kolář provided technical expertise in scRNA-seq experiments.

All Science Journal Classification (ASJC) codes

Immunology and Allergy
Immunology

Access to Document

10.1084/jem.20230194

Cite this

Brabec, T., Schwarzer, M., Kováčová, K., Dobešová, M., Schierová, D., Březina, J., Pacáková, I., Šrůtková, D., Ben-Nun, O., Goldfarb, Y., Šplíchalová, I., Kolář, M., Abramson, J., Filipp, D., & Dobeš, J. (2024). Segmented filamentous bacteria-induced epithelial MHCII regulates cognate CD4+ IELs and epithelial turnover. Journal of Experimental Medicine, 221(1), Article e20230194. https://doi.org/10.1084/jem.20230194

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title = "Segmented filamentous bacteria-induced epithelial MHCII regulates cognate CD4+ IELs and epithelial turnover",

abstract = "Intestinal epithelial cells have the capacity to upregulate MHCII molecules in response to certain epithelial-adhesive microbes, such as segmented filamentous bacteria (SFB). However, the mechanism regulating MHCII expression as well as the impact of epithelial MHCII-mediated antigen presentation on T cell responses targeting those microbes remains elusive. Here, we identify the cellular network that regulates MHCII expression on the intestinal epithelium in response to SFB. Since MHCII on the intestinal epithelium is dispensable for SFB-induced Th17 response, we explored other CD4+ T cell-based responses induced by SFB. We found that SFB drive the conversion of cognate CD4+ T cells to granzyme+ CD8α+ intraepithelial lymphocytes. These cells accumulate in small intestinal intraepithelial space in response to SFB. Yet, their accumulation is abrogated by the ablation of MHCII on the intestinal epithelium. Finally, we show that this mechanism is indispensable for the SFB-driven increase in the turnover of epithelial cells in the ileum. This study identifies a previously uncharacterized immune response to SFB, which is dependent on the epithelial MHCII function.",

author = "Tom{\'a}{\v s} Brabec and Martin Schwarzer and Katar{\'i}na Kov{\'a}{\v c}ov{\'a} and Martina Dobe{\v s}ov{\'a} and Dagmar Schierov{\'a} and Ji{\v r}{\'i} B{\v r}ezina and Iva Pac{\'a}kov{\'a} and Dagmar {\v S}růtkov{\'a} and Osher Ben-Nun and Yael Goldfarb and Iva {\v S}pl{\'i}chalov{\'a} and Michal Kol{\'a}{\v r} and Jakub Abramson and Dominik Filipp and Jan Dobe{\v s}",

note = "We are thankful to Martina Krausov{\'a} and {\v S}{\'a}rka Kocourkov{\'a} from the Genomics and Bioinformatics core facility of the Institute of Molecular Genetics in Prague, Czech Republic, for the preparation of single-cell libraries and to Zden{\v e}k Cimburek from the Flow Cytometry Core Facility of the Institute of Molecular Genetics in Prague, Czech Republic for suggestions related to cell sorting. We thank the Animal Facility in Kr{\v c} personnel of the Institute of Molecular Genetics in Prague, Czech Republic for their excellent maintenance of our animal colonies and {\v S}{\'a}rka Maisnerov{\'a} from the Laboratory of Gnotobiology, Institute of Microbiology in Nov{\'y} Hr{\'a}dek, Czech Republic for the GF and SFB-negative mice maintenance. We are thankful to Bernard Malissen (Centre d{\textquoteright}Immunologie de Marseille Luminy, Marseille, France), Ulrich Kalinke (Helmholtz Centre for Infection Research, Hannover, Germany), and Veronika Sexl (Veterinary University of Vienna, Vienna, Austria) for valuable mouse strains. Research in the Dobe{\v s} laboratory (J. Dobe{\v s}, T. Brabec, K. Kov{\'a}{\v c}ov{\'a}, M. Dobe{\v s}ov{\'a}, I. Pac{\'a}kov{\'a}) is kindly supported by the Czech Science Foundation JUNIOR STAR grant (no. 21-22435M), Czech Science Foundation grant (no. 22-30879S) and by Charles University PRIMUS grant (no. Primus/21/MED/003). M. Schwarzer and D. {\v S}růtkov{\'a} are supported by the Czech Science Foundation JUNIOR STAR grant (no. 21-19640M). D. Filipp, I. {\v S}plichalov{\'a}, and J. B{\v r}ezina are supported by grant no. 20-30350S and 22-30879S from the Czech Science Foundation. M. Kol{\'a}{\v r} is supported by the Operational Programme Research, Development and Education project (no. CZ.02.1.01/0.0/0.0/16_019/0000785). Author contributions: T. Brabec, D. Filipp, J. Abramson, and J. Dobe{\v s} initiated the project. T. Brabec and J. Dobe{\v s} designed the vast majority of experiments, critically discussed the data, and wrote and revised the manuscript in close collaboration. T. Brabec executed and analyzed the majority of the experiments, J. Dobe{\v s} executed some of the experiments and acquired the funding. J. Abramson and D. Filipp critically discussed the results, revised the manuscript, and contributed with critically important reagents. M. Schwarzer critically contributed to the design of gnotobiotic experiments and together with D. {\v S}růtkov{\'a} provided SFB monoisolates, performed all SFB colonization experiments and handled all gnotobiotic animals. K. Kov{\'a}{\v c}ov{\'a} performed majority of microscopy analysis and provided technical support for the project. M. Dobe{\v s}ov{\'a} performed some of the experiments, carried out the majority of mouse genotyping, and provided technical support for the project. J. B{\v r}ezina performed animal irradiation, critically discussed the data and the manuscript. I. Pac{\'a}kov{\'a} provided support in some of the experiments. D. Schierov{\'a}, O. Ben-Nun, Y. Goldfarb, and I. {\v S}plichalov{\'a} performed some of the experiments. M. Kol{\'a}{\v r} provided technical expertise in scRNA-seq experiments.",

year = "2024",

month = jan,

day = "1",

doi = "10.1084/jem.20230194",

language = "English",

volume = "221",

journal = "Journal of Experimental Medicine",

issn = "0022-1007",

publisher = "Rockefeller University Press",

number = "1",

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Brabec, T, Schwarzer, M, Kováčová, K, Dobešová, M, Schierová, D, Březina, J, Pacáková, I, Šrůtková, D, Ben-Nun, O , Goldfarb, Y, Šplíchalová, I, Kolář, M, Abramson, J, Filipp, D & Dobeš, J 2024, 'Segmented filamentous bacteria-induced epithelial MHCII regulates cognate CD4+ IELs and epithelial turnover', Journal of Experimental Medicine, vol. 221, no. 1, e20230194. https://doi.org/10.1084/jem.20230194

TY - JOUR

T1 - Segmented filamentous bacteria-induced epithelial MHCII regulates cognate CD4+ IELs and epithelial turnover

AU - Brabec, Tomáš

AU - Schwarzer, Martin

AU - Kováčová, Katarína

AU - Dobešová, Martina

AU - Schierová, Dagmar

AU - Březina, Jiří

AU - Pacáková, Iva

AU - Šrůtková, Dagmar

AU - Ben-Nun, Osher

AU - Goldfarb, Yael

AU - Šplíchalová, Iva

AU - Kolář, Michal

AU - Abramson, Jakub

AU - Filipp, Dominik

AU - Dobeš, Jan

N1 - We are thankful to Martina Krausová and Šárka Kocourková from the Genomics and Bioinformatics core facility of the Institute of Molecular Genetics in Prague, Czech Republic, for the preparation of single-cell libraries and to Zdeněk Cimburek from the Flow Cytometry Core Facility of the Institute of Molecular Genetics in Prague, Czech Republic for suggestions related to cell sorting. We thank the Animal Facility in Krč personnel of the Institute of Molecular Genetics in Prague, Czech Republic for their excellent maintenance of our animal colonies and Šárka Maisnerová from the Laboratory of Gnotobiology, Institute of Microbiology in Nový Hrádek, Czech Republic for the GF and SFB-negative mice maintenance. We are thankful to Bernard Malissen (Centre d’Immunologie de Marseille Luminy, Marseille, France), Ulrich Kalinke (Helmholtz Centre for Infection Research, Hannover, Germany), and Veronika Sexl (Veterinary University of Vienna, Vienna, Austria) for valuable mouse strains. Research in the Dobeš laboratory (J. Dobeš, T. Brabec, K. Kováčová, M. Dobešová, I. Pacáková) is kindly supported by the Czech Science Foundation JUNIOR STAR grant (no. 21-22435M), Czech Science Foundation grant (no. 22-30879S) and by Charles University PRIMUS grant (no. Primus/21/MED/003). M. Schwarzer and D. Šrůtková are supported by the Czech Science Foundation JUNIOR STAR grant (no. 21-19640M). D. Filipp, I. Šplichalová, and J. Březina are supported by grant no. 20-30350S and 22-30879S from the Czech Science Foundation. M. Kolář is supported by the Operational Programme Research, Development and Education project (no. CZ.02.1.01/0.0/0.0/16_019/0000785). Author contributions: T. Brabec, D. Filipp, J. Abramson, and J. Dobeš initiated the project. T. Brabec and J. Dobeš designed the vast majority of experiments, critically discussed the data, and wrote and revised the manuscript in close collaboration. T. Brabec executed and analyzed the majority of the experiments, J. Dobeš executed some of the experiments and acquired the funding. J. Abramson and D. Filipp critically discussed the results, revised the manuscript, and contributed with critically important reagents. M. Schwarzer critically contributed to the design of gnotobiotic experiments and together with D. Šrůtková provided SFB monoisolates, performed all SFB colonization experiments and handled all gnotobiotic animals. K. Kováčová performed majority of microscopy analysis and provided technical support for the project. M. Dobešová performed some of the experiments, carried out the majority of mouse genotyping, and provided technical support for the project. J. Březina performed animal irradiation, critically discussed the data and the manuscript. I. Pacáková provided support in some of the experiments. D. Schierová, O. Ben-Nun, Y. Goldfarb, and I. Šplichalová performed some of the experiments. M. Kolář provided technical expertise in scRNA-seq experiments.

PY - 2024/1/1

Y1 - 2024/1/1

N2 - Intestinal epithelial cells have the capacity to upregulate MHCII molecules in response to certain epithelial-adhesive microbes, such as segmented filamentous bacteria (SFB). However, the mechanism regulating MHCII expression as well as the impact of epithelial MHCII-mediated antigen presentation on T cell responses targeting those microbes remains elusive. Here, we identify the cellular network that regulates MHCII expression on the intestinal epithelium in response to SFB. Since MHCII on the intestinal epithelium is dispensable for SFB-induced Th17 response, we explored other CD4+ T cell-based responses induced by SFB. We found that SFB drive the conversion of cognate CD4+ T cells to granzyme+ CD8α+ intraepithelial lymphocytes. These cells accumulate in small intestinal intraepithelial space in response to SFB. Yet, their accumulation is abrogated by the ablation of MHCII on the intestinal epithelium. Finally, we show that this mechanism is indispensable for the SFB-driven increase in the turnover of epithelial cells in the ileum. This study identifies a previously uncharacterized immune response to SFB, which is dependent on the epithelial MHCII function.

AB - Intestinal epithelial cells have the capacity to upregulate MHCII molecules in response to certain epithelial-adhesive microbes, such as segmented filamentous bacteria (SFB). However, the mechanism regulating MHCII expression as well as the impact of epithelial MHCII-mediated antigen presentation on T cell responses targeting those microbes remains elusive. Here, we identify the cellular network that regulates MHCII expression on the intestinal epithelium in response to SFB. Since MHCII on the intestinal epithelium is dispensable for SFB-induced Th17 response, we explored other CD4+ T cell-based responses induced by SFB. We found that SFB drive the conversion of cognate CD4+ T cells to granzyme+ CD8α+ intraepithelial lymphocytes. These cells accumulate in small intestinal intraepithelial space in response to SFB. Yet, their accumulation is abrogated by the ablation of MHCII on the intestinal epithelium. Finally, we show that this mechanism is indispensable for the SFB-driven increase in the turnover of epithelial cells in the ileum. This study identifies a previously uncharacterized immune response to SFB, which is dependent on the epithelial MHCII function.

UR - http://www.scopus.com/inward/record.url?scp=85175500601&partnerID=8YFLogxK

U2 - 10.1084/jem.20230194

DO - 10.1084/jem.20230194

M3 - Article

C2 - 37902602

AN - SCOPUS:85175500601

SN - 0022-1007

VL - 221

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

IS - 1

M1 - e20230194

ER -

Segmented filamentous bacteria-induced epithelial MHCII regulates cognate CD4+ IELs and epithelial turnover

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