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Differential roles of regulatory T cells in acute respiratory infections
Milica Jovisic, … , Benjamin D. Singer, Luisa Morales-Nebreda
Milica Jovisic, … , Benjamin D. Singer, Luisa Morales-Nebreda
Published July 17, 2023
Citation Information: J Clin Invest. 2023;133(14):e170505. https://doi.org/10.1172/JCI170505.
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Differential roles of regulatory T cells in acute respiratory infections

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Abstract

Acute respiratory infections trigger an inflammatory immune response with the goal of pathogen clearance; however, overexuberant inflammation causes tissue damage and impairs pulmonary function. CD4+FOXP3+ regulatory T cells (Tregs) interact with cells of both the innate and the adaptive immune system to limit acute pulmonary inflammation and promote its resolution. Tregs also provide tissue protection and coordinate lung tissue repair, facilitating a return to homeostatic pulmonary function. Here, we review Treg-mediated modulation of the host response to respiratory pathogens, focusing on mechanisms underlying how Tregs promote resolution of inflammation and repair of acute lung injury. We also discuss potential strategies to harness and optimize Tregs as a cellular therapy for patients with severe acute respiratory infection and discuss open questions in the field.

Authors

Milica Jovisic, Nurbek Mambetsariev, Benjamin D. Singer, Luisa Morales-Nebreda

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Figure 1

Mechanisms of Treg-mediated immunosuppression and resolution of lung inflammation.

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Mechanisms of Treg-mediated immunosuppression and resolution of lung inf...
Tregs exert pleiotropic effects on innate (A) and adaptive (B) immune cells to dampen excessive alveolar inflammation and promote resolution following infection-induced lung inflammation and injury. (A) Tregs express the high-affinity IL-2 receptor and interact with other immune cell subsets, suppressing their activation and modulating their function. During resolution of lung inflammation, Tregs generate IL-13, signaling alveolar macrophages to secrete IL-10. Autocrine IL-10 then promotes macrophage efferocytosis of apoptotic neutrophils through activation of the VAV1/RAC1 signaling pathway and subsequent cytoskeleton remodeling to prevent excessive tissue damage. Tregs also promote a pro-resolution phenotype in macrophages by inhibiting TNF-α generation and inducing TGF-β secretion. IL-22 induction, possibly through a CD4+ Th cell intermediate, contributes to recovery and may be Treg dependent. (B) Tregs also dampen primary T cell responses to respiratory infections that include CD4+ Th1 cells, Th2 cells (and subsequent recruitment of eosinophils), CD8+ T cells, and γδ T cells, inhibiting excessive inflammation in response to pathogens. In contrast, Tregs may have a role in the generation of CD8+ memory cells, but their effect on individual compartments of the memory pool is unknown. Tregs also express surface molecules, such as CTLA-4, PD-1, CD39, and CD73, that inhibit inflammation, but the role of these molecules in responses to lung pathogens is unclear.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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