Differential roles of regulatory T cells in acute respiratory infections
Milica Jovisic, Nurbek Mambetsariev, Benjamin D. Singer, Luisa Morales-Nebreda
Milica Jovisic, Nurbek Mambetsariev, Benjamin D. Singer, Luisa Morales-Nebreda
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Differential roles of regulatory T cells in acute respiratory infections

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 2

Mechanisms of Treg-mediated lung parenchymal tissue protection and repair.

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Mechanisms of Treg-mediated lung parenchymal tissue protection and repai...
Tregs exert distinct functions to provide tissue protection and promote repair of the epithelial, endothelial, and mesenchymal compartments following infection-induced lung injury. Following lung injury, for example from influenza A virus (IAV) infection, signals from activated immune cells and damaged epithelial cells (e.g., IL-18 and IL-33) bind to their receptors on Tregs and drive Treg production of pro-epithelial growth factors (e.g., AREG and KGF) that signal to epithelial and Col14a1+ mesenchymal cells to promote epithelial regeneration. NOTCH4 regulates this axis in Tregs. The role of Tregs in modulating the population of KRT8+ transitional epithelial cells — also known as pre-alveolar type 1 transitional cell state (PATS), alveolar differentiation intermediate (ADI), damage-associated transient progenitors (DATPs), and intermediate alveolar epithelial cells (AECints) — remains unclear. Tregs also generate pro-endothelial growth factors such as VEGF that promote the regeneration of alveolar capillary endothelial cells (ECs), including those expressing carbonic anhydrase 4 (CAR4) and the endothelial tip cell markers VEGFR2, NRP1, and APLN. Tregs also decrease fibroproliferation by decreasing signaling along the CXCL12/CXCR4 axis to limit collagen deposition by bone marrow–derived collagen-producing cells. AT1 cell, alveolar epithelial type 1 cell; AT2 cell, alveolar epithelial type 2 cell.