Date Published: September 19, 2013
Publisher: Public Library of Science
Author(s): Stacey Ann Gorski, Young S. Hahn, Thomas J. Braciale, E. John Wherry.
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.
Type 2 immune responses are induced by parasitic and helminth infection and are characterized by the production of prototypical cytokines such as IL-4, -5, and -13 . IL-5 is one of the major type 2 cytokines that is essential for eosinophil survival (in humans) as well as B1-B cell development in mice . Although beneficial during parasitic or helminth infection, IL-5 may have a detrimental role in the development and severity of asthma and allergic diseases. Because of its essential role in eosinophil generation in the bone marrow and eosinophil egress out of the bone marrow, local production of IL-5 in the lungs during asthma exacerbation can result in pulmonary eosinophilia which can in turn enhance airway smooth muscle contraction and cause excess mucus production , .
IL-5 has been previously reported to be produced in the lungs during experimental IAV infection –. In the current study we focused on defining the cellular source of IL-5 in the influenza-infected lungs and the tempo of IL-5 protein and gene expression. We observed that the peak of IL-5 release into the airways (as detected in BAL fluid) corresponded to the peak of effector T cell dependent pro-inflammatory cytokine release into the BAL i.e. 6–8 d.p.i., while IL-5 gene expression persisted for a longer time frame i.e. 11–13 d.p.i. IL-5 production was associated with the progressive increase in eosinophils infiltrating the infected lungs particularly during the recovery phase, that is following infectious virus clearance (8–10 d.p.i.; ).We went on to demonstrate that the source of this IL-5 produced in the lungs during IAV infection is primarily the recently described group 2 innate lymphoid cell (ILC2) . We found that both c-kit+ and c-kit− ILC2 accumulate in the lung throughout the course of infection, however, these two ILC2 subsets appear to be recruited in a biphasic manner, that is c-kit− ILC2 are predominant during the acute phase of infection (0–7 d.p.i.) while the c-kit+ dramatically increase during the recovery phase (Figure 2B). As has been previously reported , ILC2 IL-5 production is regulated by IL-33, one source of which we now identify as the NKT cell. In support of this conclusion we found that NKT cell deficient mice have less IL-5 present in the BAL at 7 d.p.i. as well as significantly diminished IL-5 production from ILC2 during the recovery phase at 12 d.p.i.. Conversely, treatment of wild type mice with the NKT cell activating ligand αGC significantly increased IL-5 production from ILC2 and subsequently increased eosinophil numbers by 2-fold.