Innate and adaptive T cells in asthmatic patients: Relationship to severity and disease mechanisms.
BACKGROUND
Asthma is a chronic inflammatory disease involving diverse cells and mediators whose interconnectivity and relationships to asthma severity are unclear.


OBJECTIVE
We performed a comprehensive assessment of TH17 cells, regulatory T cells, mucosal-associated invariant T (MAIT) cells, other T-cell subsets, and granulocyte mediators in asthmatic patients.


METHODS
Sixty patients with mild-to-severe asthma and 24 control subjects underwent detailed clinical assessment and provided induced sputum, endobronchial biopsy, bronchoalveolar lavage, and blood samples. Adaptive and invariant T-cell subsets, cytokines, mast cells, and basophil mediators were analyzed.


RESULTS
Significant heterogeneity of T-cell phenotypes was observed, with levels of IL-13-secreting T cells and type 2 cytokines increased at some, but not all, asthma severities. TH17 cells and γδ-17 cells, proposed drivers of neutrophilic inflammation, were not strongly associated with asthma, even in severe neutrophilic forms. MAIT cell frequencies were strikingly reduced in both blood and lung tissue in relation to corticosteroid therapy and vitamin D levels, especially in patients with severe asthma in whom bronchoalveolar lavage regulatory T-cell numbers were also reduced. Bayesian network analysis identified complex relationships between pathobiologic and clinical parameters. Topological data analysis identified 6 novel clusters that are associated with diverse underlying disease mechanisms, with increased mast cell mediator levels in patients with severe asthma both in its atopic (type 2 cytokine-high) and nonatopic forms.


CONCLUSIONS
The evidence for a role for TH17 cells in patients with severe asthma is limited. Severe asthma is associated with a striking deficiency of MAIT cells and high mast cell mediator levels. This study provides proof of concept for disease mechanistic networks in asthmatic patients with clusters that could inform the development of new therapies.
Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, Southampton University Hospital, Southampton, United Kingdom; NIHR Southampton Respiratory Biomedical Research Unit, Southampton University Hospital, Southampton, United Kingdom.
Timothy S C
TS
Hinks
Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, Southampton University Hospital, Southampton, United Kingdom.
Xiaoying
X
Zhou
Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, Southampton University Hospital, Southampton, United Kingdom.
Karl J
KJ
Staples
NIHR Southampton Respiratory Biomedical Research Unit, Southampton University Hospital, Southampton, United Kingdom; Primary Care and Population Sciences, University of Southampton Faculty of Medicine, Southampton University Hospital, Southampton, United Kingdom.
Borislav D
BD
Dimitrov
MantaMatics UG, Geretsried, Germany.
Alexander
A
Manta
Ayasdi, Palo Alto, Calif.
Tanya
T
Petrossian
Ayasdi, Palo Alto, Calif.
Pek Y
PY
Lum
Primary Care and Population Sciences, University of Southampton Faculty of Medicine, Southampton University Hospital, Southampton, United Kingdom.
Caroline G
CG
Smith
Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, Southampton University Hospital, Southampton, United Kingdom; NIHR Southampton Respiratory Biomedical Research Unit, Southampton University Hospital, Southampton, United Kingdom.
Jon A
JA
Ward
Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, Southampton University Hospital, Southampton, United Kingdom; NIHR Southampton Respiratory Biomedical Research Unit, Southampton University Hospital, Southampton, United Kingdom.
Peter H
PH
Howarth
Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, Southampton University Hospital, Southampton, United Kingdom.
Andrew F
AF
Walls
Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, Southampton University Hospital, Southampton, United Kingdom; Novartis Institute of Biomedical Research, Novartis, Basel, Switzerland.
Stephan D
SD
Gadola
Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, Southampton University Hospital, Southampton, United Kingdom; NIHR Southampton Respiratory Biomedical Research Unit, Southampton University Hospital, Southampton, United Kingdom. Electronic address: r.djukanovic@soton.ac.uk.
Ratko
R
Djukanović
D056704:Adaptive Immunity; D000293:Adolescent; D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D018927:Anti-Asthmatic Agents / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D001491:Basophils / Q000276:immunology / Q000473:pathology; D001499:Bayes Theorem; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D016022:Case-Control Studies; D005260:Female; D015870:Gene Expression; D006801:Humans; D007113:Immunity, Innate; D018793:Interleukin-13 / Q000235:genetics / Q000276:immunology; D008297:Male; D008407:Mast Cells / Q000276:immunology / Q000473:pathology; D008875:Middle Aged; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics / Q000276:immunology; D012720:Severity of Illness Index; D013183:Sputum / Q000737:chemistry / Q000166:cytology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology* / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology* / Q000473:pathology
D000305:Adrenal Cortex Hormones; D018927:Anti-Asthmatic Agents; D018793:Interleukin-13; D016692:Receptors, Antigen, T-Cell, gamma-delta
Asthma; T lymphocytes; T(H)17; T(H)2; cytokines; endotype; mast cells; mucosal-associated invariant T-cell; phenotype; regulatory T