Clostridioides difficile Toxin CDT Induces Cytotoxic Responses in Human Mucosal-Associated Invariant T (MAIT) Cells

Clostridioides difficile is the major cause of antibiotic-associated colitis (CDAC) with increasing prevalence in morbidity and mortality. Severity of CDAC has been attributed to hypervirulent C. difficile strains, which in addition to toxin A and B (TcdA, TcdB) produce the binary toxin C. difficile...
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Gespeichert in:

Autor*in:	Isabel Marquardt [verfasserIn] Josefine Jakob [verfasserIn] Jessica Scheibel [verfasserIn] Julia Danielle Hofmann [verfasserIn] Frank Klawonn [verfasserIn] Meina Neumann-Schaal [verfasserIn] Ralf Gerhard [verfasserIn] Dunja Bruder [verfasserIn] Lothar Jänsch [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2021

Schlagwörter:	MAIT cells C. difficile TcdA TcdB CDT CDAC

Übergeordnetes Werk:	In: Frontiers in Microbiology - Frontiers Media S.A., 2011, 12(2021)
Übergeordnetes Werk:	volume:12 ; year:2021

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3389/fmicb.2021.752549

Katalog-ID:	DOAJ086742760

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Indexfelder

author_variant	i m im i m im i m im j j jj j j jj j j jj j s js j d h jdh f k fk m n s mns m n s mns r g rg d b db d b db l j lj
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allfields	10.3389/fmicb.2021.752549 doi (DE-627)DOAJ086742760 (DE-599)DOAJ2f8368248e8d4b778868278f1dc5bb4b DE-627 ger DE-627 rakwb eng QR1-502 Isabel Marquardt verfasserin aut Clostridioides difficile Toxin CDT Induces Cytotoxic Responses in Human Mucosal-Associated Invariant T (MAIT) Cells 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Clostridioides difficile is the major cause of antibiotic-associated colitis (CDAC) with increasing prevalence in morbidity and mortality. Severity of CDAC has been attributed to hypervirulent C. difficile strains, which in addition to toxin A and B (TcdA, TcdB) produce the binary toxin C. difficile transferase (CDT). However, the link between these toxins and host immune responses as potential drivers of immunopathology are still incompletely understood. Here, we provide first experimental evidence that C. difficile toxins efficiently activate human mucosal-associated invariant T (MAIT) cells. Among the tested toxins, CDT and more specifically, the substrate binding and pore-forming subunit CDTb provoked significant MAIT cell activation resulting in selective MAIT cell degranulation of the lytic granule components perforin and granzyme B. CDT-induced MAIT cell responses required accessory immune cells, and we suggest monocytes as a potential CDT target cell population. Within the peripheral blood mononuclear cell fraction, we found increased IL-18 levels following CDT stimulation and MAIT cell response was indeed partly dependent on this cytokine. Surprisingly, CDT-induced MAIT cell activation was found to be partially MR1-dependent, although bacterial-derived metabolite antigens were absent. However, the role of antigen presentation in this process was not analyzed here and needs to be validated in future studies. Thus, MR1-dependent induction of MAIT cell cytotoxicity might be instrumental for hypervirulent C. difficile to overcome cellular barriers and may contribute to pathophysiology of CDAC. MAIT cells C. difficile TcdA TcdB CDT CDAC Microbiology Isabel Marquardt verfasserin aut Isabel Marquardt verfasserin aut Josefine Jakob verfasserin aut Josefine Jakob verfasserin aut Josefine Jakob verfasserin aut Jessica Scheibel verfasserin aut Julia Danielle Hofmann verfasserin aut Frank Klawonn verfasserin aut Meina Neumann-Schaal verfasserin aut Meina Neumann-Schaal verfasserin aut Ralf Gerhard verfasserin aut Dunja Bruder verfasserin aut Dunja Bruder verfasserin aut Lothar Jänsch verfasserin aut In Frontiers in Microbiology Frontiers Media S.A., 2011 12(2021) (DE-627)642889384 (DE-600)2587354-4 1664302X nnns volume:12 year:2021 https://doi.org/10.3389/fmicb.2021.752549 kostenfrei https://doaj.org/article/2f8368248e8d4b778868278f1dc5bb4b kostenfrei https://www.frontiersin.org/articles/10.3389/fmicb.2021.752549/full kostenfrei https://doaj.org/toc/1664-302X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2021
spelling	10.3389/fmicb.2021.752549 doi (DE-627)DOAJ086742760 (DE-599)DOAJ2f8368248e8d4b778868278f1dc5bb4b DE-627 ger DE-627 rakwb eng QR1-502 Isabel Marquardt verfasserin aut Clostridioides difficile Toxin CDT Induces Cytotoxic Responses in Human Mucosal-Associated Invariant T (MAIT) Cells 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Clostridioides difficile is the major cause of antibiotic-associated colitis (CDAC) with increasing prevalence in morbidity and mortality. Severity of CDAC has been attributed to hypervirulent C. difficile strains, which in addition to toxin A and B (TcdA, TcdB) produce the binary toxin C. difficile transferase (CDT). However, the link between these toxins and host immune responses as potential drivers of immunopathology are still incompletely understood. Here, we provide first experimental evidence that C. difficile toxins efficiently activate human mucosal-associated invariant T (MAIT) cells. Among the tested toxins, CDT and more specifically, the substrate binding and pore-forming subunit CDTb provoked significant MAIT cell activation resulting in selective MAIT cell degranulation of the lytic granule components perforin and granzyme B. CDT-induced MAIT cell responses required accessory immune cells, and we suggest monocytes as a potential CDT target cell population. Within the peripheral blood mononuclear cell fraction, we found increased IL-18 levels following CDT stimulation and MAIT cell response was indeed partly dependent on this cytokine. Surprisingly, CDT-induced MAIT cell activation was found to be partially MR1-dependent, although bacterial-derived metabolite antigens were absent. However, the role of antigen presentation in this process was not analyzed here and needs to be validated in future studies. Thus, MR1-dependent induction of MAIT cell cytotoxicity might be instrumental for hypervirulent C. difficile to overcome cellular barriers and may contribute to pathophysiology of CDAC. MAIT cells C. difficile TcdA TcdB CDT CDAC Microbiology Isabel Marquardt verfasserin aut Isabel Marquardt verfasserin aut Josefine Jakob verfasserin aut Josefine Jakob verfasserin aut Josefine Jakob verfasserin aut Jessica Scheibel verfasserin aut Julia Danielle Hofmann verfasserin aut Frank Klawonn verfasserin aut Meina Neumann-Schaal verfasserin aut Meina Neumann-Schaal verfasserin aut Ralf Gerhard verfasserin aut Dunja Bruder verfasserin aut Dunja Bruder verfasserin aut Lothar Jänsch verfasserin aut In Frontiers in Microbiology Frontiers Media S.A., 2011 12(2021) (DE-627)642889384 (DE-600)2587354-4 1664302X nnns volume:12 year:2021 https://doi.org/10.3389/fmicb.2021.752549 kostenfrei https://doaj.org/article/2f8368248e8d4b778868278f1dc5bb4b kostenfrei https://www.frontiersin.org/articles/10.3389/fmicb.2021.752549/full kostenfrei https://doaj.org/toc/1664-302X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2021
allfields_unstemmed	10.3389/fmicb.2021.752549 doi (DE-627)DOAJ086742760 (DE-599)DOAJ2f8368248e8d4b778868278f1dc5bb4b DE-627 ger DE-627 rakwb eng QR1-502 Isabel Marquardt verfasserin aut Clostridioides difficile Toxin CDT Induces Cytotoxic Responses in Human Mucosal-Associated Invariant T (MAIT) Cells 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Clostridioides difficile is the major cause of antibiotic-associated colitis (CDAC) with increasing prevalence in morbidity and mortality. Severity of CDAC has been attributed to hypervirulent C. difficile strains, which in addition to toxin A and B (TcdA, TcdB) produce the binary toxin C. difficile transferase (CDT). However, the link between these toxins and host immune responses as potential drivers of immunopathology are still incompletely understood. Here, we provide first experimental evidence that C. difficile toxins efficiently activate human mucosal-associated invariant T (MAIT) cells. Among the tested toxins, CDT and more specifically, the substrate binding and pore-forming subunit CDTb provoked significant MAIT cell activation resulting in selective MAIT cell degranulation of the lytic granule components perforin and granzyme B. CDT-induced MAIT cell responses required accessory immune cells, and we suggest monocytes as a potential CDT target cell population. Within the peripheral blood mononuclear cell fraction, we found increased IL-18 levels following CDT stimulation and MAIT cell response was indeed partly dependent on this cytokine. Surprisingly, CDT-induced MAIT cell activation was found to be partially MR1-dependent, although bacterial-derived metabolite antigens were absent. However, the role of antigen presentation in this process was not analyzed here and needs to be validated in future studies. Thus, MR1-dependent induction of MAIT cell cytotoxicity might be instrumental for hypervirulent C. difficile to overcome cellular barriers and may contribute to pathophysiology of CDAC. MAIT cells C. difficile TcdA TcdB CDT CDAC Microbiology Isabel Marquardt verfasserin aut Isabel Marquardt verfasserin aut Josefine Jakob verfasserin aut Josefine Jakob verfasserin aut Josefine Jakob verfasserin aut Jessica Scheibel verfasserin aut Julia Danielle Hofmann verfasserin aut Frank Klawonn verfasserin aut Meina Neumann-Schaal verfasserin aut Meina Neumann-Schaal verfasserin aut Ralf Gerhard verfasserin aut Dunja Bruder verfasserin aut Dunja Bruder verfasserin aut Lothar Jänsch verfasserin aut In Frontiers in Microbiology Frontiers Media S.A., 2011 12(2021) (DE-627)642889384 (DE-600)2587354-4 1664302X nnns volume:12 year:2021 https://doi.org/10.3389/fmicb.2021.752549 kostenfrei https://doaj.org/article/2f8368248e8d4b778868278f1dc5bb4b kostenfrei https://www.frontiersin.org/articles/10.3389/fmicb.2021.752549/full kostenfrei https://doaj.org/toc/1664-302X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2021
allfieldsGer	10.3389/fmicb.2021.752549 doi (DE-627)DOAJ086742760 (DE-599)DOAJ2f8368248e8d4b778868278f1dc5bb4b DE-627 ger DE-627 rakwb eng QR1-502 Isabel Marquardt verfasserin aut Clostridioides difficile Toxin CDT Induces Cytotoxic Responses in Human Mucosal-Associated Invariant T (MAIT) Cells 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Clostridioides difficile is the major cause of antibiotic-associated colitis (CDAC) with increasing prevalence in morbidity and mortality. Severity of CDAC has been attributed to hypervirulent C. difficile strains, which in addition to toxin A and B (TcdA, TcdB) produce the binary toxin C. difficile transferase (CDT). However, the link between these toxins and host immune responses as potential drivers of immunopathology are still incompletely understood. Here, we provide first experimental evidence that C. difficile toxins efficiently activate human mucosal-associated invariant T (MAIT) cells. Among the tested toxins, CDT and more specifically, the substrate binding and pore-forming subunit CDTb provoked significant MAIT cell activation resulting in selective MAIT cell degranulation of the lytic granule components perforin and granzyme B. CDT-induced MAIT cell responses required accessory immune cells, and we suggest monocytes as a potential CDT target cell population. Within the peripheral blood mononuclear cell fraction, we found increased IL-18 levels following CDT stimulation and MAIT cell response was indeed partly dependent on this cytokine. Surprisingly, CDT-induced MAIT cell activation was found to be partially MR1-dependent, although bacterial-derived metabolite antigens were absent. However, the role of antigen presentation in this process was not analyzed here and needs to be validated in future studies. Thus, MR1-dependent induction of MAIT cell cytotoxicity might be instrumental for hypervirulent C. difficile to overcome cellular barriers and may contribute to pathophysiology of CDAC. MAIT cells C. difficile TcdA TcdB CDT CDAC Microbiology Isabel Marquardt verfasserin aut Isabel Marquardt verfasserin aut Josefine Jakob verfasserin aut Josefine Jakob verfasserin aut Josefine Jakob verfasserin aut Jessica Scheibel verfasserin aut Julia Danielle Hofmann verfasserin aut Frank Klawonn verfasserin aut Meina Neumann-Schaal verfasserin aut Meina Neumann-Schaal verfasserin aut Ralf Gerhard verfasserin aut Dunja Bruder verfasserin aut Dunja Bruder verfasserin aut Lothar Jänsch verfasserin aut In Frontiers in Microbiology Frontiers Media S.A., 2011 12(2021) (DE-627)642889384 (DE-600)2587354-4 1664302X nnns volume:12 year:2021 https://doi.org/10.3389/fmicb.2021.752549 kostenfrei https://doaj.org/article/2f8368248e8d4b778868278f1dc5bb4b kostenfrei https://www.frontiersin.org/articles/10.3389/fmicb.2021.752549/full kostenfrei https://doaj.org/toc/1664-302X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2021
allfieldsSound	10.3389/fmicb.2021.752549 doi (DE-627)DOAJ086742760 (DE-599)DOAJ2f8368248e8d4b778868278f1dc5bb4b DE-627 ger DE-627 rakwb eng QR1-502 Isabel Marquardt verfasserin aut Clostridioides difficile Toxin CDT Induces Cytotoxic Responses in Human Mucosal-Associated Invariant T (MAIT) Cells 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Clostridioides difficile is the major cause of antibiotic-associated colitis (CDAC) with increasing prevalence in morbidity and mortality. Severity of CDAC has been attributed to hypervirulent C. difficile strains, which in addition to toxin A and B (TcdA, TcdB) produce the binary toxin C. difficile transferase (CDT). However, the link between these toxins and host immune responses as potential drivers of immunopathology are still incompletely understood. Here, we provide first experimental evidence that C. difficile toxins efficiently activate human mucosal-associated invariant T (MAIT) cells. Among the tested toxins, CDT and more specifically, the substrate binding and pore-forming subunit CDTb provoked significant MAIT cell activation resulting in selective MAIT cell degranulation of the lytic granule components perforin and granzyme B. CDT-induced MAIT cell responses required accessory immune cells, and we suggest monocytes as a potential CDT target cell population. Within the peripheral blood mononuclear cell fraction, we found increased IL-18 levels following CDT stimulation and MAIT cell response was indeed partly dependent on this cytokine. Surprisingly, CDT-induced MAIT cell activation was found to be partially MR1-dependent, although bacterial-derived metabolite antigens were absent. However, the role of antigen presentation in this process was not analyzed here and needs to be validated in future studies. Thus, MR1-dependent induction of MAIT cell cytotoxicity might be instrumental for hypervirulent C. difficile to overcome cellular barriers and may contribute to pathophysiology of CDAC. MAIT cells C. difficile TcdA TcdB CDT CDAC Microbiology Isabel Marquardt verfasserin aut Isabel Marquardt verfasserin aut Josefine Jakob verfasserin aut Josefine Jakob verfasserin aut Josefine Jakob verfasserin aut Jessica Scheibel verfasserin aut Julia Danielle Hofmann verfasserin aut Frank Klawonn verfasserin aut Meina Neumann-Schaal verfasserin aut Meina Neumann-Schaal verfasserin aut Ralf Gerhard verfasserin aut Dunja Bruder verfasserin aut Dunja Bruder verfasserin aut Lothar Jänsch verfasserin aut In Frontiers in Microbiology Frontiers Media S.A., 2011 12(2021) (DE-627)642889384 (DE-600)2587354-4 1664302X nnns volume:12 year:2021 https://doi.org/10.3389/fmicb.2021.752549 kostenfrei https://doaj.org/article/2f8368248e8d4b778868278f1dc5bb4b kostenfrei https://www.frontiersin.org/articles/10.3389/fmicb.2021.752549/full kostenfrei https://doaj.org/toc/1664-302X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2021
language	English
source	In Frontiers in Microbiology 12(2021) volume:12 year:2021
sourceStr	In Frontiers in Microbiology 12(2021) volume:12 year:2021
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	MAIT cells C. difficile TcdA TcdB CDT CDAC Microbiology
isfreeaccess_bool	true
container_title	Frontiers in Microbiology
authorswithroles_txt_mv	Isabel Marquardt @@aut@@ Josefine Jakob @@aut@@ Jessica Scheibel @@aut@@ Julia Danielle Hofmann @@aut@@ Frank Klawonn @@aut@@ Meina Neumann-Schaal @@aut@@ Ralf Gerhard @@aut@@ Dunja Bruder @@aut@@ Lothar Jänsch @@aut@@
publishDateDaySort_date	2021-01-01T00:00:00Z
hierarchy_top_id	642889384
id	DOAJ086742760
language_de	englisch
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topic_title	QR1-502 Clostridioides difficile Toxin CDT Induces Cytotoxic Responses in Human Mucosal-Associated Invariant T (MAIT) Cells MAIT cells C. difficile TcdA TcdB CDT CDAC
topic	misc QR1-502 misc MAIT cells misc C. difficile misc TcdA misc TcdB misc CDT misc CDAC misc Microbiology
topic_unstemmed	misc QR1-502 misc MAIT cells misc C. difficile misc TcdA misc TcdB misc CDT misc CDAC misc Microbiology
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title	Clostridioides difficile Toxin CDT Induces Cytotoxic Responses in Human Mucosal-Associated Invariant T (MAIT) Cells
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title_full	Clostridioides difficile Toxin CDT Induces Cytotoxic Responses in Human Mucosal-Associated Invariant T (MAIT) Cells
author_sort	Isabel Marquardt
journal	Frontiers in Microbiology
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author_browse	Isabel Marquardt Josefine Jakob Jessica Scheibel Julia Danielle Hofmann Frank Klawonn Meina Neumann-Schaal Ralf Gerhard Dunja Bruder Lothar Jänsch
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title_sort	clostridioides difficile toxin cdt induces cytotoxic responses in human mucosal-associated invariant t (mait) cells
callnumber	QR1-502
title_auth	Clostridioides difficile Toxin CDT Induces Cytotoxic Responses in Human Mucosal-Associated Invariant T (MAIT) Cells
abstract	Clostridioides difficile is the major cause of antibiotic-associated colitis (CDAC) with increasing prevalence in morbidity and mortality. Severity of CDAC has been attributed to hypervirulent C. difficile strains, which in addition to toxin A and B (TcdA, TcdB) produce the binary toxin C. difficile transferase (CDT). However, the link between these toxins and host immune responses as potential drivers of immunopathology are still incompletely understood. Here, we provide first experimental evidence that C. difficile toxins efficiently activate human mucosal-associated invariant T (MAIT) cells. Among the tested toxins, CDT and more specifically, the substrate binding and pore-forming subunit CDTb provoked significant MAIT cell activation resulting in selective MAIT cell degranulation of the lytic granule components perforin and granzyme B. CDT-induced MAIT cell responses required accessory immune cells, and we suggest monocytes as a potential CDT target cell population. Within the peripheral blood mononuclear cell fraction, we found increased IL-18 levels following CDT stimulation and MAIT cell response was indeed partly dependent on this cytokine. Surprisingly, CDT-induced MAIT cell activation was found to be partially MR1-dependent, although bacterial-derived metabolite antigens were absent. However, the role of antigen presentation in this process was not analyzed here and needs to be validated in future studies. Thus, MR1-dependent induction of MAIT cell cytotoxicity might be instrumental for hypervirulent C. difficile to overcome cellular barriers and may contribute to pathophysiology of CDAC.
abstractGer	Clostridioides difficile is the major cause of antibiotic-associated colitis (CDAC) with increasing prevalence in morbidity and mortality. Severity of CDAC has been attributed to hypervirulent C. difficile strains, which in addition to toxin A and B (TcdA, TcdB) produce the binary toxin C. difficile transferase (CDT). However, the link between these toxins and host immune responses as potential drivers of immunopathology are still incompletely understood. Here, we provide first experimental evidence that C. difficile toxins efficiently activate human mucosal-associated invariant T (MAIT) cells. Among the tested toxins, CDT and more specifically, the substrate binding and pore-forming subunit CDTb provoked significant MAIT cell activation resulting in selective MAIT cell degranulation of the lytic granule components perforin and granzyme B. CDT-induced MAIT cell responses required accessory immune cells, and we suggest monocytes as a potential CDT target cell population. Within the peripheral blood mononuclear cell fraction, we found increased IL-18 levels following CDT stimulation and MAIT cell response was indeed partly dependent on this cytokine. Surprisingly, CDT-induced MAIT cell activation was found to be partially MR1-dependent, although bacterial-derived metabolite antigens were absent. However, the role of antigen presentation in this process was not analyzed here and needs to be validated in future studies. Thus, MR1-dependent induction of MAIT cell cytotoxicity might be instrumental for hypervirulent C. difficile to overcome cellular barriers and may contribute to pathophysiology of CDAC.
abstract_unstemmed	Clostridioides difficile is the major cause of antibiotic-associated colitis (CDAC) with increasing prevalence in morbidity and mortality. Severity of CDAC has been attributed to hypervirulent C. difficile strains, which in addition to toxin A and B (TcdA, TcdB) produce the binary toxin C. difficile transferase (CDT). However, the link between these toxins and host immune responses as potential drivers of immunopathology are still incompletely understood. Here, we provide first experimental evidence that C. difficile toxins efficiently activate human mucosal-associated invariant T (MAIT) cells. Among the tested toxins, CDT and more specifically, the substrate binding and pore-forming subunit CDTb provoked significant MAIT cell activation resulting in selective MAIT cell degranulation of the lytic granule components perforin and granzyme B. CDT-induced MAIT cell responses required accessory immune cells, and we suggest monocytes as a potential CDT target cell population. Within the peripheral blood mononuclear cell fraction, we found increased IL-18 levels following CDT stimulation and MAIT cell response was indeed partly dependent on this cytokine. Surprisingly, CDT-induced MAIT cell activation was found to be partially MR1-dependent, although bacterial-derived metabolite antigens were absent. However, the role of antigen presentation in this process was not analyzed here and needs to be validated in future studies. Thus, MR1-dependent induction of MAIT cell cytotoxicity might be instrumental for hypervirulent C. difficile to overcome cellular barriers and may contribute to pathophysiology of CDAC.
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title_short	Clostridioides difficile Toxin CDT Induces Cytotoxic Responses in Human Mucosal-Associated Invariant T (MAIT) Cells
url	https://doi.org/10.3389/fmicb.2021.752549 https://doaj.org/article/2f8368248e8d4b778868278f1dc5bb4b https://www.frontiersin.org/articles/10.3389/fmicb.2021.752549/full https://doaj.org/toc/1664-302X
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author2	Isabel Marquardt Josefine Jakob Jessica Scheibel Julia Danielle Hofmann Frank Klawonn Meina Neumann-Schaal Ralf Gerhard Dunja Bruder Lothar Jänsch
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