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Human lung conventional dendritic cells orchestrate lymphoid Neogenesis during chronic obstructive pulmonary disease

Human lung conventional dendritic cells orchestrate lymphoid Neogenesis during chronic obstructive pulmonary disease
Human lung conventional dendritic cells orchestrate lymphoid Neogenesis during chronic obstructive pulmonary disease

Rationale: Emerging evidence supports a crucial role for tertiary lymphoid organs (TLOs) in chronic obstructive pulmonary disease (COPD) progression. However, mechanisms of immune cell activation leading to TLOs in COPD remain to be defined. Objectives: To examine the role of lung dendritic cells (DCs) in T follicular helper (Tfh)-cell induction, a T-cell subset critically implicated in lymphoid organ formation, in COPD. Methods: Myeloid cell heterogeneity and phenotype were studied in an unbiased manner via single-cell RNA sequencing on HLA-DR1 cells sorted from human lungs.Wemeasured the in vitro capability of control and COPD lung DC subsets, sorted using a fluorescenceactivated cell sorter, to polarize IL-211CXCL131 (IL-21-positive and C-X-C chemokine ligand type 13-positive) Tfh-like cells. In situ imaging analysis was performed on Global Initiative for Chronic Obstructive Lung Disease stage IV COPD lungs with TLOs. Measurements and Main Results: Single-cell RNA-sequencing analysis revealed a high degree of heterogeneity among human lung myeloid cells. Among these, conventional dendritic type 2 cells (cDC2s) showed increased induction of IL-211CXCL131 Tfh-like cells. Importantly, the capacity to induce IL-211 Tfh-like cells was higher in cDC2s from patients with COPD than in those from control patients. Increased Tfh-cell induction by COPD cDC2s correlated with increased presence of Tfh-like cells in COPD lungs as compared with those in control lungs, and cDC2s colocalized with Tfh-like cells in TLOs of COPD lungs. Mechanistically, cDC2s exhibited a unique migratory signature and (transcriptional) expression of several pathways and genes related to DC-induced Tfh-cell priming. Importantly, blocking the costimulatory OX40L (OX40 ligand)-OX40 axis reduced Tfh-cell induction by control lung cDC2s. Conclusions: In COPD lungs, we found lung EBI21 (Epstein-Barr virus-induced gene 2-positive) OX-40L-expressing cDC2s that induced IL-211 Tfh-like cells, suggesting an involvement of these cells in TLO formation.

T follicular helper cells, chronic obstructive pulmonary disease (COPD), dendritic cells, tertiary lymphoid organs
1073-449X
535-548
Naessens, Thomas
c6e480d5-b806-43ed-9802-b10ea5ed8d89
Morias, Yannick
cd1f7925-230a-4904-8f73-5f46cdab082f
Hamrud, Eva
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Gehrmann, Ulf
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Budida, Ramachandramouli
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Mattsson, Johan
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Baker, Tina
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Skogberg, Gabriel
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Israelsson, Elisabeth
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Thorn, Kristofer
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Schuijs, Martin
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Angermann, Bastian
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Melville, Faye
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Staples, Karl J
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Cunoosamy, Danen M.
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Lambrecht, Bart
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Naessens, Thomas
c6e480d5-b806-43ed-9802-b10ea5ed8d89
Morias, Yannick
cd1f7925-230a-4904-8f73-5f46cdab082f
Hamrud, Eva
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Gehrmann, Ulf
aa15ef43-fe4f-4a97-beae-51a918ea4407
Budida, Ramachandramouli
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Mattsson, Johan
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Baker, Tina
2e82a061-0718-4924-a031-7a36e4893721
Skogberg, Gabriel
4d15f691-f3e7-4164-a302-0756b0886a94
Israelsson, Elisabeth
a4bb8c32-a16c-40f1-897e-bb2da1f682b8
Thorn, Kristofer
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Schuijs, Martin
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Angermann, Bastian
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Melville, Faye
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Staples, Karl J
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Cunoosamy, Danen M.
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Lambrecht, Bart
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Naessens, Thomas, Morias, Yannick, Hamrud, Eva, Gehrmann, Ulf, Budida, Ramachandramouli, Mattsson, Johan, Baker, Tina, Skogberg, Gabriel, Israelsson, Elisabeth, Thorn, Kristofer, Schuijs, Martin, Angermann, Bastian, Melville, Faye, Staples, Karl J, Cunoosamy, Danen M. and Lambrecht, Bart (2020) Human lung conventional dendritic cells orchestrate lymphoid Neogenesis during chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine, 202 (4), 535-548. (doi:10.1164/rccm.201906-1123OC).

Record type: Article

Abstract

Rationale: Emerging evidence supports a crucial role for tertiary lymphoid organs (TLOs) in chronic obstructive pulmonary disease (COPD) progression. However, mechanisms of immune cell activation leading to TLOs in COPD remain to be defined. Objectives: To examine the role of lung dendritic cells (DCs) in T follicular helper (Tfh)-cell induction, a T-cell subset critically implicated in lymphoid organ formation, in COPD. Methods: Myeloid cell heterogeneity and phenotype were studied in an unbiased manner via single-cell RNA sequencing on HLA-DR1 cells sorted from human lungs.Wemeasured the in vitro capability of control and COPD lung DC subsets, sorted using a fluorescenceactivated cell sorter, to polarize IL-211CXCL131 (IL-21-positive and C-X-C chemokine ligand type 13-positive) Tfh-like cells. In situ imaging analysis was performed on Global Initiative for Chronic Obstructive Lung Disease stage IV COPD lungs with TLOs. Measurements and Main Results: Single-cell RNA-sequencing analysis revealed a high degree of heterogeneity among human lung myeloid cells. Among these, conventional dendritic type 2 cells (cDC2s) showed increased induction of IL-211CXCL131 Tfh-like cells. Importantly, the capacity to induce IL-211 Tfh-like cells was higher in cDC2s from patients with COPD than in those from control patients. Increased Tfh-cell induction by COPD cDC2s correlated with increased presence of Tfh-like cells in COPD lungs as compared with those in control lungs, and cDC2s colocalized with Tfh-like cells in TLOs of COPD lungs. Mechanistically, cDC2s exhibited a unique migratory signature and (transcriptional) expression of several pathways and genes related to DC-induced Tfh-cell priming. Importantly, blocking the costimulatory OX40L (OX40 ligand)-OX40 axis reduced Tfh-cell induction by control lung cDC2s. Conclusions: In COPD lungs, we found lung EBI21 (Epstein-Barr virus-induced gene 2-positive) OX-40L-expressing cDC2s that induced IL-211 Tfh-like cells, suggesting an involvement of these cells in TLO formation.

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Naessens et al 2020 AJRCCM combined - Accepted Manuscript
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Accepted/In Press date: 6 April 2020
e-pub ahead of print date: 7 April 2020
Published date: 15 August 2020
Keywords: T follicular helper cells, chronic obstructive pulmonary disease (COPD), dendritic cells, tertiary lymphoid organs

Identifiers

Local EPrints ID: 439225
URI: http://eprints.soton.ac.uk/id/eprint/439225
ISSN: 1073-449X
PURE UUID: df86c063-4392-41aa-904f-b838ebfb8a47
ORCID for Karl J Staples: ORCID iD orcid.org/0000-0003-3844-6457

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Date deposited: 07 Apr 2020 16:30
Last modified: 17 Mar 2024 05:29

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Contributors

Author: Thomas Naessens
Author: Yannick Morias
Author: Eva Hamrud
Author: Ulf Gehrmann
Author: Ramachandramouli Budida
Author: Johan Mattsson
Author: Tina Baker
Author: Gabriel Skogberg
Author: Elisabeth Israelsson
Author: Kristofer Thorn
Author: Martin Schuijs
Author: Bastian Angermann
Author: Faye Melville
Author: Karl J Staples ORCID iD
Author: Danen M. Cunoosamy
Author: Bart Lambrecht

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