PMID- 27683080 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220131 IS - 1553-7374 (Electronic) IS - 1553-7366 (Print) IS - 1553-7366 (Linking) VI - 12 IP - 9 DP - 2016 Sep TI - Tbet Deficiency Causes T Helper Cell Dependent Airways Eosinophilia and Mucus Hypersecretion in Response to Rhinovirus Infection. PG - e1005913 LID - 10.1371/journal.ppat.1005913 [doi] LID - e1005913 AB - 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 (RORgammat), 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 gammadeltaT 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. FAU - Glanville, Nicholas AU - Glanville N AD - Airway Disease Infection Section, National Heart and Lung Institute, MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, London, United Kingdom. FAU - Peel, Tamlyn J AU - Peel TJ AUID- ORCID: 0000-0003-4188-612X AD - Airway Disease Infection Section, National Heart and Lung Institute, MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, London, United Kingdom. FAU - Schroder, Armin AU - Schroder A AD - Laboratory of Cellular and Molecular Lung Immunology, Department of Molecular Pneumology, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Germany. FAU - Aniscenko, Julia AU - Aniscenko J AUID- ORCID: 0000-0001-8641-1123 AD - Airway Disease Infection Section, National Heart and Lung Institute, MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, London, United Kingdom. FAU - Walton, Ross P AU - Walton RP AD - Airway Disease Infection Section, National Heart and Lung Institute, MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, London, United Kingdom. FAU - Finotto, Susetta AU - Finotto S AUID- ORCID: 0000-0001-7623-7977 AD - Laboratory of Cellular and Molecular Lung Immunology, Department of Molecular Pneumology, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Germany. FAU - Johnston, Sebastian L AU - Johnston SL AD - Airway Disease Infection Section, National Heart and Lung Institute, MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, London, United Kingdom. LA - eng GR - G1000758/MRC_/Medical Research Council/United Kingdom PT - Journal Article DEP - 20160928 PL - United States TA - PLoS Pathog JT - PLoS pathogens JID - 101238921 PMC - PMC5040449 COIS- Professor Johnston has recieved grants and personal fees from Centocor, grants and personal fees from Sanofi Pasteur, grants and personal fees from GSK, grants and personal fees from Chiesi, grants and personal fees from Boehringer Ingelheim, personal fees from Grunenthal, grants and personal fees from Novartis, grants, personal fees and Shareholding from Synairgen, outside the submitted work. In addition, Professor Johnston has patents as follows. Blair ED, Killington RA, Rowlands DJ, Clarke NJ, Johnston SL. Transgenic animal models of HRV with human ICAM-1 sequences. UK patent application No. 02 167 29.4, 18 July 2002 and International patent application No. PCT/EP2003/007939, 17 July 2003. licensed, a patent Wark PA, Johnston SL, Holgate ST, Davies DE. Anti-virus therapy for respiratory diseases. UK patent application No. GB 0405634.7, 12 March 2004. licensed, a patent Wark PA, Johnston SL, Holgate ST, Davies DE. Interferon-Beta for Anti-Virus Therapy for Respiratory Diseases. International Patent Application No. PCT/GB05/50031, 12 March 2004. licensed, a patent Wark PA, Johnston SL, Holgate ST, Davies DE. The use of Interferon Lambda for the treatment and prevention of virally-induced exacerbation in asthma and chronic pulmonary obstructive disease. UK patent application No. 0518425.4, 9 September 2005. licensed, a patent Wark PA, Johnston SL, Holgate ST, Davies DE. Anti-Virus Therapy for Respiratory Diseases. US Patent Application - 11/517,763, Patent No.7569216, National Phase of PCT/GB2005/050031, 04 August 2009. licensed, a patent Wark PA, Johnston SL, Holgate ST, Davies DE. Interferon-beta for Anti-Virus Therapy for Respiratory Diseases. European Patent Number 1734987, 5 May 2010. licensed, a patent Wark PA, Johnston SL, Holgate ST, Davies DE. Anti-Virus Therapy for Respiratory Diseases (IFNb therapy) Hong Kong Patent Number 1097181, 31 August 2010. licensed, a patent Wark PA, Johnston SL, Holgate ST, Davies DE. Anti-Virus Therapy for Respiratory Diseases (IFNb therapy). Japanese Patent Number 4807526, 26 August 2011. licensed, a patent Wark PA, Johnston SL, Holgate ST, Davies DE. Interferon-beta for Anti-Virus Therapy for Respiratory Diseases. New Hong Kong - Divisional Patent Application No. 11100187.0, 10 January 2011. licensed, and a patent Burdin N, Almond J, Lecouturieir, V, Girerd-Chambaz Y, Guy, B, Bartlett N, Walton R, McLean G, Glanville N, Johnston SL. Induction of cross-reactive cellular response against rhinovirus antigens European Patent Number 13305152, 4 April 2013. pending. NG and RPW are also inventors of the patent, Induction of cross-reactive cellular response against rhinovirus antigens. EDAT- 2016/09/30 06:00 MHDA- 2016/09/30 06:01 PMCR- 2016/09/28 CRDT- 2016/09/30 06:00 PHST- 2016/06/01 00:00 [received] PHST- 2016/09/04 00:00 [accepted] PHST- 2016/09/30 06:00 [entrez] PHST- 2016/09/30 06:00 [pubmed] PHST- 2016/09/30 06:01 [medline] PHST- 2016/09/28 00:00 [pmc-release] AID - PPATHOGENS-D-16-01234 [pii] AID - 10.1371/journal.ppat.1005913 [doi] PST - epublish SO - PLoS Pathog. 2016 Sep 28;12(9):e1005913. doi: 10.1371/journal.ppat.1005913. eCollection 2016 Sep.