Abstract
There is evidence indicating that invariant Natural Killer T (iNKT) cells play an important role in defense against influenza A virus (IAV). However, the effect of inhibitory receptor, programmed death-1 (PD-1), and its ligands, programmed death ligand (PD-L) 1 and 2 on iNKT cells in protection against IAV remains to be elucidated. Here we investigated the effects of these co-stimulatory molecules on iNKT cells in the response to influenza. We discovered that compare to the wild type, PD-L1 deficient mice show reduced sensitivity to IAV infection as evident by reduced weight loss, decreased pulmonary inflammation and cellular infiltration. In contrast, PD-L2 deficient mice showed augmented weight loss, pulmonary inflammation and cellular infiltration compare to the wild type mice after influenza infection. Adoptive transfer of iNKT cells from wild type, PD-L1 or PD-L2 deficient mice into iNKT cell deficient mice recapitulated these findings. Interestingly, in our transfer system PD-L1−/−-derived iNKT cells produced high levels of interferon-gamma whereas PD-L2−/−-derived iNKT cells produced high amounts of interleukin-4 and 13 suggesting a role for these cytokines in sensitivity to influenza. We identified that PD-L1 negatively regulates the frequency of iNKT cell subsets in the lungs of IAV infected mice. Altogether, these results demonstrate that lack of PD-L1 expression by iNKT cells reduces the sensitivity to IAV and that the presence of PD-L2 is important for dampening the deleterious inflammatory responses after IAV infection. Our findings potentially have clinical implications for developing new therapies for influenza.
Highlights
Influenza A virus (IAV) infections represent a major public health threat, in the case of children, the elderly and those with underlying diseases, all of whom are at an increased risk for disease complications and death following IAV infection [1,2]
We first tested whether invariant natural killer T (iNKT) cells are recruited to the lungs after IAV infection and whether these cells play a protective role in mice with BALB/c background
Our findings suggest an important role for the programmed death-1 (PD-1) ligands, PD-L1 and PD-L2 in regulating the immune response to infection with IAV
Summary
Influenza A virus (IAV) infections represent a major public health threat, in the case of children, the elderly and those with underlying diseases, all of whom are at an increased risk for disease complications and death following IAV infection [1,2]. Immune system plays an important role in the resolution of IAV infection. Both mucosal and systemic immunity play important roles in the elimination of infection with IAV [4,5,6]. Accumulating evidence in the last few years suggests an important role for conventional CD4+ and CD8+ T cells in the control and clearance of the IAV [7,8,9]. In recent years, a relatively new T cell population, invariant natural killer T (iNKT) cells, have been reported to act as innate lymphocytes and as regulators of adaptive immune responses [10,11]
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