Novel mechanisms regulating immunity to respiratory virus infection

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Influenza viruses are rapidly mutating RNA viruses and the causative agent of about one billion annual respiratory virus infections and 500,000 deaths worldwide. Influenza virus has significant pandemic potential, seasonal epidemics burden the human population, and viral resistance has developed to all available treatment options. Much emphasis is placed on the humoral immune response to influenza, as neutralizing antibodies are the desired vaccine outcome. However, B cell-deficient mice and humans with hyper-IgM syndrome clear influenza virus infections, while T cell-deficient mice do not. Thus, B cell-independent mechanisms protect against influenza virus-related lethality. We recently generated novel and compelling evidence that IAV infection triggers lung mast cells (MCs) to produce IL-10 (MC-IL-10) in wild type (WT) and T- and B-cell deficient (Rag1- KO) mice. MC-IL-10 induces the expression of the IL-10 receptor (IL-10R) and programmed cell death ligands 1 and 2 (PD-L1 and PD-L2) on Natural Killer (NK) cells. Notably, in Rag1-KO mice, where NK cells are the sole virus-fighting lymphocytes, PD-L1 blockade, but not PD-1 or PD-L2 blockade, significantly reduces IAV-related lethality. The IAV/MC-IL10/NK-PD-L1 pathway is also conserved in humans, at least in vitro: IAV infection of human-lung tissue-derived single-primary-cell suspensions or intact human lung tissue slices elicit MC-IL-10 and NK cell-expressed IL-10R, PD-L1, and PD-L2. We found T cells also upregulate IL-10R and modulate their PD- 1 and PD-L1 expression upon IAV infection. Seeking to understand why this regulatory pathway is evolutionarily conserved, we found cytotoxic T lymphocytes (CTLs) implicated as the main contributors to IAV induced immunopathology. Indeed, IL-10-KO/Rag-WT mice, whose NK and T cells do not upregulate IL-10R, PD-1, PD- L1, or PD-L2, develop prolonged immune infiltration and immunopathology after IAV clearance. We hypothesize that influenza virus-induced MC-IL-10 balances sterilizing immunity and harmful immunopathology, tightly regulating NK and T cell functions through their MC-IL-10 induced PD-1 (CTLs) and PD-L1 (NK cells and CTLs) expression and signaling. Our findings are novel and surprising. The induction of the PD/PD-L pathway is generally associated with lymphocyte exhaustion (via T cell expressed PD-1) in cancer or chronic infection. However, little is known about how IL-10 and PD-L1 signals to modulate lymphocyte functions, especially in acute viral illness. To address this knowledge gap, we propose to determine how IL-10 and PD-L1-signaling regulates NK and T cell functions and their contributions to viral clearance vs. lung pathology upon influenza virus infection. The knowledge gained will be highly relevant to human health. Our data will provide the rationale to develop novel therapeutics augmenting the antiviral immune response while preventing detrimental immunopathology.