Date Published: March 31, 2016
Publisher: Public Library of Science
Author(s): Samuel Philip Nobs, Christoph Schneider, Alex Kaspar Heer, Jatta Huotari, Ari Helenius, Manfred Kopf, Guus F. Rimmelzwaan.
Phosphoinositide-3-kinases have been shown to be involved in influenza virus pathogenesis. They are targeted directly by virus proteins and are essential for efficient viral replication in infected lung epithelial cells. However, to date the role of PI3K signaling in influenza infection in vivo has not been thoroughly addressed. Here we show that one of the PI3K subunits, p110γ, is in fact critically required for mediating the host’s antiviral response. PI3Kγ deficient animals exhibit a delayed viral clearance and increased morbidity during respiratory infection with influenza virus. We demonstrate that p110γ is required for the generation and maintenance of potent antiviral CD8+ T cell responses through the developmental regulation of pulmonary cross-presenting CD103+ dendritic cells under homeostatic and inflammatory conditions. The defect in lung dendritic cells leads to deficient CD8+ T cell priming, which is associated with higher viral titers and more severe disease course during the infection. We thus identify PI3Kγ as a novel key host protective factor in influenza virus infection and shed light on an unappreciated layer of complexity concerning the role of PI3K signaling in this context.
Phosphoinositide 3-kinases (PI3K) are classified into three main groups (class I, class II and class III) according to sequence homology of the catalytic subunit and their substrate specificity . Class I PI3K are further divided into class IA and class IB. Class IA PI3K form dimers consisting of either one of the catalytic subunits p110α, p110β or p110δ, and the common regulatory subunit p85    . They typically act downstream of receptor tyrosine kinases and are important regulators of cell growth, division and survival . In contrast, class IB PI3K (also termed PI3Kγ) comprises only one catalytic subunit, p110γ, which associates with the regulatory subunits p101 or p84     . PI3Kγ signals downstream of G-protein coupled receptors (GPCR) such as chemokine receptors or receptor tyrosine kinases . Both class IA and PI3Kγ can be activated by ras  . Classes II and III PI3K are ubiquitously expressed and mainly involved in regulation of protein trafficking and cell homeostasis. PI3Kγ on the other hand is preferentially expressed in hematopoietic cells, although expression was also shown in peribronchial epithelial cells, the endothelium, the brain and the heart  .
In this study we describe PI3Kγ as novel factor, which plays a key role in successful host defense against respiratory infection with influenza virus. We show that the highly increased susceptibility of p110γ-kinase dead animals stems from a defective T cell response leading to higher viral titers and more pronounced morbidity. This phenotype is due to a deficiency in the lung-resident DCs, which are essential for the initial priming of the adaptive immune response against influenza . We could show that PI3Kγ is functionally not required in DCs to activate T cells in vitro and in vivo, however, the pronounced reduction of lung DCs in naïve PI3Kγ-deficient animals leads to an impaired transport of antigen to the draining lymph node and thus to a defective antiviral T cell response and consequently a delayed viral clearance.