Mycobacterium tuberculosis impedes CD40-dependent notch signaling to restrict Th17 polarization during infection
Summary: Early Th17 responses are necessary to provide protection against Mycobacterium tuberculosis (Mtb). Mtb impedes Th17 polarization by restricting CD40 co-stimulatory pathway on dendritic cells (DCs). We previously demonstrated that engaging CD40 on DCs increased Th17 responses. However, the m...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-05-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004222005752 |
| _version_ | 1811341137834672128 |
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| author | Ana Beatriz Enriquez Jonathan Kevin Sia Hedwin Kitdorlang Dkhar Shu Ling Goh Melanie Quezada Kristina Larrieux Stallings Jyothi Rengarajan |
| author_facet | Ana Beatriz Enriquez Jonathan Kevin Sia Hedwin Kitdorlang Dkhar Shu Ling Goh Melanie Quezada Kristina Larrieux Stallings Jyothi Rengarajan |
| author_sort | Ana Beatriz Enriquez |
| collection | DOAJ |
| description | Summary: Early Th17 responses are necessary to provide protection against Mycobacterium tuberculosis (Mtb). Mtb impedes Th17 polarization by restricting CD40 co-stimulatory pathway on dendritic cells (DCs). We previously demonstrated that engaging CD40 on DCs increased Th17 responses. However, the molecular mechanisms that contributed to Th17 polarization were unknown. Here, we identify the Notch ligand DLL4 as necessary for Th17 polarization and demonstrate that Mtb limits DLL4 on DCs to prevent optimal Th17 responses. Although Mtb infection induced only low levels of DLL4, engaging CD40 on DCs increased DLL4 expression. Antibody blockade of DLL4 on DCs reduced Th17 polarization in vitro and in vivo. In addition, we show that the Mtb Hip1 protease attenuates DLL4 expression on lung DCs by impeding CD40 signaling. Overall, our results demonstrate that Mtb impedes CD40-dependent DLL4 expression to restrict Th17 responses and identify the CD40-DLL4 pathways as targets for developing new Th17-inducing vaccines and adjuvants for tuberculosis. |
| first_indexed | 2024-04-13T18:52:18Z |
| format | Article |
| id | doaj.art-f7533561f8714bf38b651afe3f6a81f7 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-04-13T18:52:18Z |
| publishDate | 2022-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-f7533561f8714bf38b651afe3f6a81f72022-12-22T02:34:23ZengElsevieriScience2589-00422022-05-01255104305Mycobacterium tuberculosis impedes CD40-dependent notch signaling to restrict Th17 polarization during infectionAna Beatriz Enriquez0Jonathan Kevin Sia1Hedwin Kitdorlang Dkhar2Shu Ling Goh3Melanie Quezada4Kristina Larrieux Stallings5Jyothi Rengarajan6Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USAEmory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA; Memorial Sloan Kettering Cancer Center, New York, NY 10065, USAEmory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USAEmory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USAEmory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USAEmory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USAEmory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA; Department of Medicine, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, GA 30322, USA; Corresponding authorSummary: Early Th17 responses are necessary to provide protection against Mycobacterium tuberculosis (Mtb). Mtb impedes Th17 polarization by restricting CD40 co-stimulatory pathway on dendritic cells (DCs). We previously demonstrated that engaging CD40 on DCs increased Th17 responses. However, the molecular mechanisms that contributed to Th17 polarization were unknown. Here, we identify the Notch ligand DLL4 as necessary for Th17 polarization and demonstrate that Mtb limits DLL4 on DCs to prevent optimal Th17 responses. Although Mtb infection induced only low levels of DLL4, engaging CD40 on DCs increased DLL4 expression. Antibody blockade of DLL4 on DCs reduced Th17 polarization in vitro and in vivo. In addition, we show that the Mtb Hip1 protease attenuates DLL4 expression on lung DCs by impeding CD40 signaling. Overall, our results demonstrate that Mtb impedes CD40-dependent DLL4 expression to restrict Th17 responses and identify the CD40-DLL4 pathways as targets for developing new Th17-inducing vaccines and adjuvants for tuberculosis.http://www.sciencedirect.com/science/article/pii/S2589004222005752Molecular biologyParasitology |
| spellingShingle | Ana Beatriz Enriquez Jonathan Kevin Sia Hedwin Kitdorlang Dkhar Shu Ling Goh Melanie Quezada Kristina Larrieux Stallings Jyothi Rengarajan Mycobacterium tuberculosis impedes CD40-dependent notch signaling to restrict Th17 polarization during infection iScience Molecular biology Parasitology |
| title | Mycobacterium tuberculosis impedes CD40-dependent notch signaling to restrict Th17 polarization during infection |
| title_full | Mycobacterium tuberculosis impedes CD40-dependent notch signaling to restrict Th17 polarization during infection |
| title_fullStr | Mycobacterium tuberculosis impedes CD40-dependent notch signaling to restrict Th17 polarization during infection |
| title_full_unstemmed | Mycobacterium tuberculosis impedes CD40-dependent notch signaling to restrict Th17 polarization during infection |
| title_short | Mycobacterium tuberculosis impedes CD40-dependent notch signaling to restrict Th17 polarization during infection |
| title_sort | mycobacterium tuberculosis impedes cd40 dependent notch signaling to restrict th17 polarization during infection |
| topic | Molecular biology Parasitology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004222005752 |
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