Editors' ChoiceInfectious Disease

Bystanders get in the game

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Science Translational Medicine  08 Jan 2020:
Vol. 12, Issue 525, eaba2904
DOI: 10.1126/scitranslmed.aba2904


Tissue-resident memory T cells respond in a nonspecific manner to reduce bacteria in the lungs of mice.

Tissue-resident memory T cells (TRM) are a recently discovered lineage of memory T cells that reside and exert their effector function in the tissue. In contrast, “traditional” memory T cells recirculate throughout the body in the vasculature and lymphoid organs, infiltrating peripheral tissues after infection or injury. Within the tissue, antiviral TRM respond rapidly to secondary infections by the same virus through the production of antiviral cytokines. One TRM-produced cytokine, interferon-γ (IFN-γ), transcriptionally activates other interferon-regulated genes, including chemokines that recruit more circulating memory T cells into the immune response, providing protection against infection.

Although IFN-γ limits viral infection, production is tightly controlled, as exuberant responses can exacerbate infection. In memory T cells, IFN-γ is posttranscriptionally regulated to ensure secretion only after recognition of cognate viral antigen. Despite this, during certain viral infections, some central and effector memory T cells can become activated in a nonspecific fashion, a process called bystander activation. TRM are thought to produce IFN-γ in a highly specific manner only after infection with homologous virus, thus eliminating the possibility for tissue damage incurred by localized IFN-γ overproduction.

In order to examine potential bystander activation of lung-resident TRM, Ge et al. generated mice with influenza-specific TRM in the lung. Unexpectedly, administration of either lipopolysaccharide or heat-killed bacteria resulted in IFN-γ production by a small but significant percentage of TRM present in the lung parenchyma. Maximal TRM activation occurred at 12 hours, after which IFN-γ production declined. Using a combination of approaches, the authors demonstrated that lung dendritic cells recognized inhaled bacteria and produced interleukin-12, which elicited TRM IFN-γ production in the absence of influenza infection. To understand whether bystander TRM activation could influence bacterial infection, the authors established bacterial pneumonia in mice with or without influenza-specific TRM. Bystander TRM IFN-γ production rapidly recruited elevated numbers of neutrophils into the lung, which cleared lung bacteria. These data demonstrate that bystander TRM can influence the course of a nonantigenically related bacterial infection. More studies will be needed to uncover the mechanisms through which IFN-γ induces lung neutrophil immigration, as well as the physical requirements for dendritic cell/TRM proximity to elicit this protective effect. Nonetheless, these results suggest bystander TRM activation should be more widely considered during diverse nonviral infections.

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