Research Article: Tbet Deficiency Causes T Helper Cell Dependent Airways Eosinophilia and Mucus Hypersecretion in Response to Rhinovirus Infection

Date Published: September 28, 2016

Publisher: Public Library of Science

Author(s): Nicholas Glanville, Tamlyn J. Peel, Armin Schröder, Julia Aniscenko, Ross P. Walton, Susetta Finotto, Sebastian L. Johnston, Paul G. Thomas.


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.

Partial Text

Human rhinovirus (RV) infections cause the common cold and are associated with two thirds of asthma and one third of chronic obstructive pulmonary disease (COPD) exacerbations [1,2]. There are currently no specific licensed therapies or vaccines available for RV infections. Current understanding of adaptive immune responses to RV is very limited. Almost all studies have focused on the role of antibodies, showing that neutralising antibodies generated in response to infection can be protective against symptoms, but because of the antigenic heterogeneity amongst the >150 RVs people continue to suffer infections throughout life [3,4]. It is unknown what, if any, contribution conventional T cells make to virus control or to the severity of RV-induced colds. Similarly, whilst T helper cell responses have been associated with disease outcomes in asthma exacerbations, the contribution of RV-specific T cells has not specifically been studied. Studies of memory cells in humans have suggested that RV-specific T cells in tonsil and peripheral blood are primarily CD4+ helper cells which express the Th1 cytokine interferon (IFN)-γ upon re-stimulation with RV [5–7]. However, production of the Th2 cytokines interleukin (IL)-4, IL-5 and IL-13 by RV-specific memory cells has also been described and IL-4 and IL-13 have been detected in supernatants of RV-exposed peripheral blood mononuclear cells (PBMC) from asthmatics, suggesting that Th2 responses to RV develop in some individuals [5,6,8]. RV infection in fact induces both Th1 promoting factors such as C-X-C motif ligand (CXCL)10 and IL-12, and Th2 promoting factors C-C motif ligand (CCL)17, CCL22, IL-33 and IL-25 in vivo and/or in vitro [9–13]. RVs therefore appear to have the capacity to induce both Th1 and Th2 orientated responses. For other respiratory viruses such as respiratory syncytial virus (RSV) for which T cell immunity is better understood, T cells have complex roles, both aiding virus clearance but also causing immunopathology, with alterations in the balance between type 1 and type 2 T cell responses having been linked to severity of virus associated immunopathology [14]. The limited available evidence for RV suggests that Th1 responses are desirable because we have shown in the mouse that enhancing the memory Th1 response by means of vaccination is associated with enhanced neutralising antibody responses and in humans, that greater Th1 and lessened Th2 number following polyclonal stimulation are associated with improved disease outcome during experimental RV-induced asthma exacerbations[15,16]. It remains to be fully established however what type of response is most desirable in terms of limiting virus replication and potentially reducing disease, and what exactly the implications of an aberrant T helper response might be.

We utilised a Tbet deficient mouse strain to examine the role of Th1 cell responses in RV infection. We found that in the absence of Tbet, Th2 and Th17 responses developed in the airways and that this altered T cell response was associated with an impaired antibody response and drove an inflammatory phenotype characterised by airways eosinophilia and enhanced mucus production.




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