Tbet Deficiency Causes T Helper Cell Dependent Airways Eosinophilia and Mucus Hypersecretion in Response to Rhinovirus Infection.
Current understanding of adaptive immune, particularly T cell, responses to human rhinoviruses (RV) is limited. Memory T cells are thought to be of a primarily T helper 1 type, but both T helper 1 and T helper 2 memory cells have been described, and heightened T helper 2/ lessened T helper 1 responses have been associated with increased RV-induced asthma exacerbation severity. We examined the contribution of T helper 1 cells to RV-induced airways inflammation using mice deficient in the transcription factor T-Box Expressed In T Cells (Tbet), a critical controller of T helper 1 cell differentiation. Using flow cytometry we showed that Tbet deficient mice lacked the T helper 1 response of wild type mice and instead developed mixed T helper 2/T helper 17 responses to RV infection, evidenced by increased numbers of GATA binding protein 3 (GATA-3) and RAR-related orphan receptor gamma t (RORγt), and interleukin-13 and interleukin-17A expressing CD4+ T cells in the lung. Forkhead box P3 (FOXP3) and interleukin-10 expressing T cell numbers were unaffected. Tbet deficient mice also displayed deficiencies in lung Natural Killer, Natural Killer T cell and γδT cell responses, and serum neutralising antibody responses. Tbet deficient mice exhibited pronounced airways eosinophilia and mucus production in response to RV infection that, by utilising a CD4+ cell depleting antibody, were found to be T helper cell dependent. RV induction of T helper 2 and T helper 17 responses may therefore have an important role in directly driving features of allergic airways disease such as eosinophilia and mucus hypersecretion during asthma exacerbations.
Airway Disease Infection Section, National Heart and Lung Institute, MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, London, United Kingdom.
Nicholas
N
Glanville
Airway Disease Infection Section, National Heart and Lung Institute, MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, London, United Kingdom.
Tamlyn J
http://orcid.org/0000-0003-4188-612X
TJ
Peel
Laboratory of Cellular and Molecular Lung Immunology, Department of Molecular Pneumology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Armin
A
Schröder
Airway Disease Infection Section, National Heart and Lung Institute, MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, London, United Kingdom.
Julia
http://orcid.org/0000-0001-8641-1123
J
Aniscenko
Airway Disease Infection Section, National Heart and Lung Institute, MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, London, United Kingdom.
Ross P
RP
Walton
Laboratory of Cellular and Molecular Lung Immunology, Department of Molecular Pneumology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Susetta
http://orcid.org/0000-0001-7623-7977
S
Finotto
Airway Disease Infection Section, National Heart and Lung Institute, MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, London, United Kingdom.
Sebastian L
SL
Johnston
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