Immune Mechanisms of Control of Lung Inflammation following Influenza A Virus Infection

Moser, Emily, Pharmacology - Graduate School of Arts and Sciences, University of Virginia
Braciale, Thomas, Department of Pathology, Research, University of Virginia

Influenza A Virus (IAV) infection in the respiratory tract triggers robust immune responses, resulting in virus clearance and pulmonary inflammation, which may induce acute lung injury (ALI). Both co-stimulatory molecules and cytokines regulate the development and/or resolution of IAV infection-induced ALI. In order to elucidate novel mechanisms by which immune responses contribute to influenza infection-induced ALI, we investigated the effects of two immune system components on the development and/or resolution of ALI in a mouse model of IAV infection: 1) the role of CD86-dependent Regulatory T cells (Tregs), and 2) the role of IL-21 receptor (IL-21R) signaling.
B7 family co-stimulatory molecules such as CD80 and CD86 have important roles in modulating T cell activity during the initiation and effector stages of the host response to IAV. We found that during ongoing inflammation after IAV infection, antibody-mediated CD86 blockade after virus clearance led to a decrease in Tregs and a delay in recovery, characterized by increased numbers of lung neutrophils and inflammatory cytokines in the respiratory tract. Furthermore, neutrophil depletion in Treg-depleted mice reduced excess inflammatory cytokines in the airways. These results demonstrate that CD86-dependent Tregs contribute to the resolution of disease after IAV infection, in part by suppressing neutrophil-driven cytokine release into the airways.
IL-21 is a cytokine with many different immune-modulatory functions, although its role in IAV infection has not been fully evaluated. We evaluated the contributions of IL-21/IL-21R signaling to the development of ALI after IAV infection using IL-21R knockout (KO) mice. We found that lack of IL-21R signaling had no impact on virus clearance or the development of ALI. However, several inflammatory cytokines were elevated in the bronchoalveolar lavage fluid of IL-21R KO mice, correlating with increased gamma-delta (γδ) T cells capable of producing IL-17. These findings demonstrate that IL-21R does not contribute to ALI after IAV infection, but reveal a previously unrecognized role of IL-21R signaling in regulating IL-17 production by γδ T cells.
These studies add to our understanding of the immune system control of ALI induced by IAV infection and identify novel therapeutic targets to promote recovery from influenza infection-induced ALI.

PHD (Doctor of Philosophy)
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