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Cytotoxic CD4+ tissue-resident memory T cells are associated with asthma severity

Cytotoxic CD4+ tissue-resident memory T cells are associated with asthma severity
Cytotoxic CD4+ tissue-resident memory T cells are associated with asthma severity
Background: patients with severe uncontrolled asthma represent a distinct endotype with persistent airway inflammation and remodeling that is refractory to corticosteroid treatment. CD4+ TH2 cells play a central role in orchestrating asthma pathogenesis, and biologic therapies targeting their cytokine pathways have had promising outcomes. However, not all patients respond well to such treatment, and their effects are not always durable nor reverse airway remodeling. This observation raises the possibility that other CD4+ T cell subsets and their effector molecules may drive airway inflammation and remodeling.

Methods: we performed single-cell transcriptome analysis of >50,000 airway CD4+ T cells isolated from bronchoalveolar lavage samples from 30 patients with mild and severe asthma.

Findings: we observed striking heterogeneity in the nature of CD4+ T cells present in asthmatics’ airways, with tissue-resident memory T (TRM) cells making a dominant contribution. Notably, in severe asthmatics, a subset of CD4+ TRM cells (CD103-expressing) was significantly increased, comprising nearly 65% of all CD4+ T cells in the airways of male patients with severe asthma when compared to mild asthma (13%). This subset was enriched for transcripts linked to T cell receptor activation (HLA-DRB1, HLA-DPA1) and cytotoxicity (GZMB, GZMA) and, following stimulation, expressed high levels of transcripts encoding for pro-inflammatory non-TH2 cytokines (CCL3, CCL4, CCL5, TNF, LIGHT) that could fuel persistent airway inflammation and remodeling.

Conclusions: our findings indicate the need to look beyond the traditional T2 model of severe asthma to better understand the heterogeneity of this disease.

Funding: this research was funded by the NIH.
CD4+ tissue-resident memory T cells, Translation to patients, airway T cells, asthma, cytotoxic CD4+ T cells, severe asthma, single-cell RNA sequencing
2666-6340
875-897.e8
Herrera-De La Mata, Sara
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Ramírez-Suástegui, Ciro
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Mistry, Heena
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Castañeda-Castro, Francisco Emmanuel
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Kyyaly, Mohammad A.
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Simon, Hayley
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Liang, Shu
ef10b70c-61f7-4c74-89bf-11870742a9c5
Lau, Laurie
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Barber, Clair
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Mondal, Monalisa
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Zhang, Hongmei
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Arshad, Syed Hasan
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Kurukulaaratchy, Ramesh J.
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Vijayanand, Pandurangan
514cf88a-b802-4daa-b1b4-76ed4d60324a
Seumois, Grégory
31238629-b7dd-434a-8057-6e62f8ad57b6
Herrera-De La Mata, Sara
1d12f612-8346-485c-b712-0a2e27173918
Ramírez-Suástegui, Ciro
a836459b-e3bc-4b0e-a7c2-cf82d8155cb8
Mistry, Heena
216f0018-b071-406c-9b66-0e025ca959a7
Castañeda-Castro, Francisco Emmanuel
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Kyyaly, Mohammad A.
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Simon, Hayley
2fcaa431-76e1-434e-97cf-ca4433d7583d
Liang, Shu
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Lau, Laurie
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Barber, Clair
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Mondal, Monalisa
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Zhang, Hongmei
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Arshad, Syed Hasan
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Kurukulaaratchy, Ramesh J.
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Vijayanand, Pandurangan
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Seumois, Grégory
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Herrera-De La Mata, Sara, Ramírez-Suástegui, Ciro, Mistry, Heena, Castañeda-Castro, Francisco Emmanuel, Kyyaly, Mohammad A., Simon, Hayley, Liang, Shu, Lau, Laurie, Barber, Clair, Mondal, Monalisa, Zhang, Hongmei, Arshad, Syed Hasan, Kurukulaaratchy, Ramesh J., Vijayanand, Pandurangan and Seumois, Grégory (2023) Cytotoxic CD4+ tissue-resident memory T cells are associated with asthma severity. Med, 4 (12), 875-897.e8. (doi:10.1016/j.medj.2023.09.003).

Record type: Article

Abstract

Background: patients with severe uncontrolled asthma represent a distinct endotype with persistent airway inflammation and remodeling that is refractory to corticosteroid treatment. CD4+ TH2 cells play a central role in orchestrating asthma pathogenesis, and biologic therapies targeting their cytokine pathways have had promising outcomes. However, not all patients respond well to such treatment, and their effects are not always durable nor reverse airway remodeling. This observation raises the possibility that other CD4+ T cell subsets and their effector molecules may drive airway inflammation and remodeling.

Methods: we performed single-cell transcriptome analysis of >50,000 airway CD4+ T cells isolated from bronchoalveolar lavage samples from 30 patients with mild and severe asthma.

Findings: we observed striking heterogeneity in the nature of CD4+ T cells present in asthmatics’ airways, with tissue-resident memory T (TRM) cells making a dominant contribution. Notably, in severe asthmatics, a subset of CD4+ TRM cells (CD103-expressing) was significantly increased, comprising nearly 65% of all CD4+ T cells in the airways of male patients with severe asthma when compared to mild asthma (13%). This subset was enriched for transcripts linked to T cell receptor activation (HLA-DRB1, HLA-DPA1) and cytotoxicity (GZMB, GZMA) and, following stimulation, expressed high levels of transcripts encoding for pro-inflammatory non-TH2 cytokines (CCL3, CCL4, CCL5, TNF, LIGHT) that could fuel persistent airway inflammation and remodeling.

Conclusions: our findings indicate the need to look beyond the traditional T2 model of severe asthma to better understand the heterogeneity of this disease.

Funding: this research was funded by the NIH.

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Herrera-De La Mata et al._FullText_ForRamesh_09JAN2024 (1) - Accepted Manuscript
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Accepted/In Press date: 18 September 2023
e-pub ahead of print date: 20 October 2023
Published date: 8 December 2023
Additional Information: Funding Information: We thank Dr. C. Kim, Dr. D. Hinz, members of the flow cytometry core facility at La Jolla Institute for Immunology, and the members of the Vijayanand laboratory, for scientific support. We also thank all donors for their charitable contribution to academic research. This work was supported by NIH research grants R01HL114093 and U19-AI070535 (P.V.) and equipment grants (S10RR027366 - BD FACSAria II, and S10OD025052 - Illumina Novaseq 6000); the William K. Bowes, Jr. Foundation (P.V.); and BioLegend – BioLegend Fellow (S.H.-M.). The WATCH study is supported by the Southampton NIHR Biomedical Research Centre and the Southampton NIHR Clinical Research Facility, which are funded by the NIHR and are a partnership between the University of Southampton and University Hospital Southampton NHS Foundation Trust. Conceptualization, R.J.K. S.H.A. P.V. and G.S.; project lead, S.H.-D.L.M. C.R.-S. H.M. R.J.K. S.H.A. P.V. and G.S.; methodology and sample and clinical data collection, H.M. M.A.K. L.L. C.B. R.J.K. S.H.A. and G.S.; resources, H.M. R.J.K. S.H.A. P.V. and G.S.; performed experiments, S.H.-D.L.M. H.M. and G.S.; performed sequencing library preparation and sequencing runs, S.H.-D.L.M. H.S. S.L. and M.M.; performed computational and bioinformatics analysis, C.R.-S. and F.E.C.-C.; performed statistical analysis, S.H.-M. C.R.-S. and H.Z.; unrestricted access to data, S.H.-D.L.M. C.R.-S. H.M. F.E.C.-C. S.H.A. R.J.K. P.V. and G.S.; data analysis and interpretation, S.H.-D.L.M. C.R.-S. H.M. F.E.C.-C. P.V. and G.S.; writing and editing of manuscript, S.H.-D.L.M. C.R.-S. H.M. P.V. and G.S.; review of manuscript, all authors; funding and supervision, R.J.K. S.H.A. P.V. and G.S. All authors read and approved the final article and take responsibility for its content. S.H.A. received research funding unrelated to this work from Dyson Inc. We worked to ensure gender balance in the recruitment of human subjects. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in their field of research or within their geographical location. One or more of the authors of this paper self-identifies as a gender minority in their field of research. One or more of the authors of this paper self-identifies as a member of the LGBTQIA+ community. We support inclusive, diverse, and equitable conduct of research. Funding Information: We thank Dr. C. Kim, Dr. D. Hinz, members of the flow cytometry core facility at La Jolla Institute for Immunology, and the members of the Vijayanand laboratory, for scientific support. We also thank all donors for their charitable contribution to academic research. This work was supported by NIH research grants R01HL114093 and U19-AI070535 (P.V.) and equipment grants ( S10RR027366 - BD FACSAria II , and S10OD025052 - Illumina Novaseq 6000); the William K. Bowes, Jr. Foundation (P.V.); and BioLegend – BioLegend Fellow (S.H.-M.). The WATCH study is supported by the Southampton NIHR Biomedical Research Centre and the Southampton NIHR Clinical Research Facility , which are funded by the NIHR and are a partnership between the University of Southampton and University Hospital Southampton NHS Foundation Trust. Publisher Copyright: © 2023 Elsevier Inc.
Keywords: CD4+ tissue-resident memory T cells, Translation to patients, airway T cells, asthma, cytotoxic CD4+ T cells, severe asthma, single-cell RNA sequencing

Identifiers

Local EPrints ID: 486157
URI: http://eprints.soton.ac.uk/id/eprint/486157
ISSN: 2666-6340
PURE UUID: baf6cfd6-0ecb-4f95-85b4-ce6f2b42ef7a
ORCID for Clair Barber: ORCID iD orcid.org/0000-0001-5335-5129
ORCID for Ramesh J. Kurukulaaratchy: ORCID iD orcid.org/0000-0002-1588-2400

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Date deposited: 11 Jan 2024 17:48
Last modified: 18 Mar 2024 02:51

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Contributors

Author: Sara Herrera-De La Mata
Author: Ciro Ramírez-Suástegui
Author: Heena Mistry
Author: Francisco Emmanuel Castañeda-Castro
Author: Mohammad A. Kyyaly
Author: Hayley Simon
Author: Shu Liang
Author: Laurie Lau
Author: Clair Barber ORCID iD
Author: Monalisa Mondal
Author: Hongmei Zhang
Author: Pandurangan Vijayanand
Author: Grégory Seumois

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