Innate and adaptive T cells in asthmatic patients: Relationship to severity and disease mechanisms

• Published in: Journal of allergy and clinical immunology Vol. 136; no. 2; pp. 323 - 333
• Main Authors: Hinks, Timothy S.C., Zhou, Xiaoying, Staples, Karl J., Dimitrov, Borislav D., Manta, Alexander, Petrossian, Tanya, Lum, Pek Y., Smith, Caroline G., Ward, Jon A., Howarth, Peter H., Walls, Andrew F., Gadola, Stephan D., Djukanović, Ratko
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2015; Elsevier Limited; Mosby
• Subjects: Adaptive Immunity; Adolescent; Adrenal Cortex Hormones - therapeutic use; Adult; Aged; Allergy and Immunology; Anti-Asthmatic Agents - therapeutic use; Asthma; Asthma - drug therapy; Asthma - genetics; Asthma - immunology; Asthma - pathology; Asthma and Lower Airway Disease; Basophils - immunology; Basophils - pathology; Bayes Theorem; Biomedical research; Biopsy; Bronchoalveolar Lavage Fluid - chemistry; Bronchoalveolar Lavage Fluid - cytology; Case-Control Studies; Cytokines; Disease; endotype; Female; Gene Expression; Humans; Immunity, Innate; Interleukin-13 - genetics; Interleukin-13 - immunology; Lymphocytes; Male; mast cells; Mast Cells - immunology; Mast Cells - pathology; Methods; Middle Aged; mucosal-associated invariant T-cell; phenotype; Receptors, Antigen, T-Cell, gamma-delta - genetics; Receptors, Antigen, T-Cell, gamma-delta - immunology; regulatory T; Severity of Illness Index; Software; Sputum - chemistry; Sputum - cytology; Studies; T lymphocytes; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - pathology; TH17; Th17 Cells - immunology; Th17 Cells - pathology; TH2; Th2 Cells - immunology; Th2 Cells - pathology; T lymphocytes; phenotype; regulatory T; eNO; Treg; IQR; mast cells; BAL; FOXP3; Asthma; ACQ; Tc; TDA; mucosal-associated invariant T-cell; BNA; GINA; endotype; ICS; cytokines; MAIT; TH17; TH2; Bayesian network analysis; Cytotoxic T; Mucosal-associated invariant T; T H17; T H2; Bronchoalveolar lavage; Forkhead box protein 3; Topological data analysis; Exhaled nitric oxide; Inhaled corticosteroid; Asthma Control Questionnaire; Global Initiative for Asthma; Interquartile range; T(H)17; T(H)2
• DOI: 10.1016/j.jaci.2015.01.014
• ISSN: 0091-6749

Asthma is a chronic inflammatory disease involving diverse cells and mediators whose interconnectivity and relationships to asthma severity are unclear. 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. 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. 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. 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.