Respiratory virus infections, such as influenza, typically induce a robust type I (pro-inflammatory cytokine) immune response, however, the production of type 2 cytokines has been observed. Type 2 cytokine production during respiratory virus infection is linked to asthma exacerbation; however, type 2 cytokines may also be tissue protective. Interleukin (IL)-5 is a prototypical type 2 cytokine that is essential for eosinophil maturation and egress out of the bone marrow. However, little is known about the cellular source and underlying cellular and molecular basis for the regulation of IL-5 production during respiratory virus infection. Using a mouse model of influenza virus infection, we found a robust transient release of IL-5 into infected airways along with a significant and progressive accumulation of eosinophils into the lungs, particularly during the recovery phase of infection, i.e. following virus clearance. The cellular source of the IL-5 was group 2 innate lymphoid cells (ILC2) infiltrating the infected lungs. Interestingly, the progressive accumulation of eosinophils following virus clearance is reflected in the rapid expansion of c-kit+ IL-5 producing ILC2. We further demonstrate that the enhanced capacity for IL-5 production by ILC2 during recovery is concomitant with the enhanced expression of the IL-33 receptor subunit, ST2, by ILC2. Lastly, we show that NKT cells, as well as alveolar macrophages (AM), are endogenous sources of IL-33 that enhance IL-5 production from ILC2. Collectively, these results reveal that c-kit+ ILC2 interaction with IL-33 producing NKT and AM leads to abundant production of IL-5 by ILC2 and accounts for the accumulation of eosinophils observed during the recovery phase of influenza infection.

Summary The contribution of different DC subsets to effector and memory CD8+ T cell generation during infection and the mechanism by which DC controls these fate decisions is unclear. Here we demonstrated that the CD103+ and CD11bhi migratory respiratory DC (RDC) subsets after influenza virus infection activated naïve virus-specific CD8+ T cells differentially. CD103+ RDC supported the generation of CD8+ T effectors (Teff), which migrate from lymph nodes to the infected lungs. In contrast, migrant CD11bhi RDC activated CD8+ T cells characteristic of central memory CD8+ cells (CD8+ Tcm) including retention within the draining lymph nodes. CD103+ RDC expressed CD24 at an elevated level, contributing to the propensity of this DC subpopulation to support CD8+ Teff differentiation. Mechanistically, CD24 was shown to regulate CD8+ T cell activation through HMGB1 mediated engagement of T cell RAGE. Thus there is distribution of labor among DC subsets in regulating CD8+ T cell differentiation.

No abstract

A hallmark of infection by respiratory viruses is productive infection of and the subsequent destruction of the airway epithelium. These viruses can also target other stromal cell types as well as in certain instances, CD45+ hematopoietic cells either resident in the lungs or part of the inflammatory response to infection. The mechanisms by which the virus produces injury to these cell types include direct infection with cytopathic effects as a consequence of replication. Host mediated damage is also a culprit in pulmonary injury as both innate and adaptive immune cells produce soluble and cell-associated pro-inflammatory mediators. Recently, it has become increasingly clear that in addition to control of excess inflammation and virus elimination, the resolution of infection requires an active repair process, which is necessary to regain normal respiratory function and restore the lungs to homeostasis. The repair response must re-establish the epithelial barrier and regenerate the microarchitecture of the lung. Emerging areas of research have highlighted the importance of innate immune cells, particularly the newly described innate lymphoid cells, as well as alternatively activated macrophages and pulmonary stem cells in the repair process. The mechanisms by which respiratory viruses may impede or alter the repair response will be important areas of research for identifying therapeutic targets aimed at limiting virus and host mediated injury and expediting recovery.