Regulatory T cells expressing granzyme B play a critical role in controlling lung inflammation during acute viral infection

Abstract

The inflammatory response to lung infections must be tightly regulated, enabling pathogen elimination while maintaining crucial gas exchange. Using recently described “depletion of regulatory T cell” (DEREG) mice, we found that selective depletion of regulatory T cells (Tregs) during acute respiratory syncytial virus (RSV) infection enhanced viral clearance but increased weight loss, local cytokine and chemokine release, and T-cell activation and cellular influx into the lungs. Conversely, inflammation was decreased when Treg numbers and activity were boosted using interleukin-2 immune complexes. Unexpectedly, lung (but not draining lymph node) Tregs from RSV-infected mice expressed granzyme B (GzmB), and bone marrow chimeric mice with selective loss of GzmB in the Treg compartment displayed markedly enhanced cellular infiltration into the lung after infection. A crucial role for GzmB-expressing Tregs has not hitherto been described in the lung or during acute infections, but may explain the inability of children with perforin/GzmB defects to regulate immune responses to infection. The effects of RSV infection in mice with defective immune regulation closely parallel the observed effects of RSV in children with bronchiolitis, suggesting that the pathogenesis of bronchiolitis may involve an inability to regulate virus-induced inflammation.

CD137 Agonist Therapy Can Reprogram Regulatory T Cells into Cytotoxic CD4+ T Cells with Antitumor Activity

“…4A). These results provide indirect evidence that the Foxp3 + Eomes + CD4 + T cells may not mediate immunosuppressive effects on conventional T cells and are therefore distinct from the Treg population described by Loebbermann et al (39). It has recently been shown that granzyme B-producing Tregs can kill tumor target cells (40).…”

“…2D). Loebbermann et al has shown that granzyme B-expressing Tregs in the lungs of RSV-infected animals play a critical role in dampening inflammation (39). Their main function was clearly immune suppressive because they killed inflammatory effector T cells (39).…”

The role of Th17 and Treg responses in the pathogenesis of RSV infection

“…However, no difference in the final viral clearance was seen postinfection as it was achieved completely in both the controls and, albeit slower, in the Treg-depleted mice (34,36,37). Loebbermann et al (38) on the other hand, did describe a decrease in viral load when depleting Treg cells in mice. These findings can be explained by the fact that during an RSV infection, Treg cells are responsible for early recruitment of activated CD8 + cytotoxic cells out of the draining lymph nodes to the lungs (37).…”

“…The Treg and Th17 subsets have distinct and opposing features in this context, as demonstrated by their effects on viral clearance, clinical severity, and Th2-oriented immune response (see Table 1). Specifically, the Treg immune response will ensure an efficient viral clearance and inhibition of the Th2-oriented immune response resulting in a less severe clinical picture (34,(36)(37)(38)(39). Although evidence is less conclusive than is the case for the Treg immune response, the Th17 immune response is thought to hamper an efficient viral clearance and further enhance a Th2 immune response resulting in a more severe clinical picture (50).…”

“…In contrast to depleting Treg cells, stimulating the Treg cells in function and numbers by using IL-2/anti-IL-2 immune complexes limits lung inflammation and disease severity without preventing viral clearance (38).…”