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.