Thesis
The role of CRTH2+ CD8+ T cells in severe asthma
- Abstract:
-
Type 2 inflammation of the airways is present in most patients with asthma, and some patients with chronic obstructive pulmonary disease (COPD). The molecular drivers of the type 2 immune response include the cytokines IL-4, IL-5, and IL-13, produced by activated type 2 T helper (Th2) and type 2 cytotoxic T (Tc2) cells. Expression of the prostaglandin D2 (PGD2) receptor chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) has been associated with type 2 T cells, and CRTH2+ T cells in the blood and lung have been linked to the severity and endotype of asthma. In a new study of 127 participants, blood CRTH2+ T cell counts were not associated with asthma severity or endotype, and instead appeared to be driven by other factors such as smoking history and biological sex. Airway CRTH2+ T cells were detectable in the sputum, and airway CRTH2+ Th cells correlated with sputum eosinophils. The sensitivity and specificity of CRTH2 as a marker of type 2 T cells was assessed ex vivo, showing that CRTH2 is a more sensitive marker of Tc2 (~80 %) than Th2 (~50 %) cells. CRTH2+ CD8+ T cells were isolated from peripheral blood mononuclear cells (PBMCs) and expanded without addition of polarising cytokines, retaining a stable type 2 identity. Cultured CRTH2+ CD8+ T cells could be stimulated by multiple pathways: through the T-cell receptor, by PGD2-CRTH2 interactions, or by alarmin cytokines. The transcriptomic response of CRTH2+ CD8+ T cells was specific to each stimulation. The gene expression patterns of activated CRTH2+ CD8+ T cells highlighted their capacity to contribute to type 2 inflammation, but also revealed novel links to genes and biological processes associated with asthma. These data support future study of CRTH2+ CD8+ T cells in the human airways.
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Authors
Contributors
- Institution:
- University of Oxford
- Division:
- MSD
- Department:
- NDM
- Sub department:
- NDM Experimental Medicine
- Oxford college:
- New College
- Role:
- Supervisor
- Institution:
- University of Oxford
- Division:
- MSD
- Department:
- NDM
- Sub department:
- NDM Experimental Medicine
- Role:
- Supervisor
- Institution:
- University of Oxford
- Division:
- MSD
- Department:
- NDM
- Sub department:
- NDM Experimental Medicine
- Oxford college:
- Green Templeton College
- Role:
- Supervisor
- ORCID:
- 0000-0003-4307-9161
- Institution:
- University of Oxford
- Division:
- MSD
- Department:
- NDM
- Sub department:
- NDM Experimental Medicine
- Oxford college:
- St Edmund Hall
- Role:
- Supervisor
- Institution:
- Faculty of Medicine at the National Heart & Lung Institute, Imperial College London
- Role:
- Examiner
- Funder identifier:
- http://dx.doi.org/10.13039/501100000265
- Grant:
- BRT00030
- Programme:
- Oxford MRC DTP – Magdalen-RCUK - NDM Prize Studentship
- DOI:
- Type of award:
- DPhil
- Level of award:
- Doctoral
- Awarding institution:
- University of Oxford
- Language:
-
English
- Keywords:
- Subjects:
- Deposit date:
-
2022-01-17
Terms of use
- Copyright holder:
- Hoyle, RD
- Copyright date:
- 2021
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