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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Review Series

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 3

Potential strategies to promote the efficacy and safety of Treg cellular therapies for patients with infection-induced lung injury.

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Potential strategies to promote the efficacy and safety of Treg cellular...
(A) Tregs can be genetically engineered to express a synthetic receptor — artificial T cell receptor (TCR), chimeric antigen receptor (CAR), C-X-C motif chemokine receptor 3 (CXCR3), or CC chemokine receptor 4 (CCR4) — that recognizes an antigenic target of interest or enhances trafficking to the inflamed lung. (B) Pharmacological modifiers, including DNA methyltransferase inhibitors (DNMTi), ten-eleven translocation (TET) activators, histone deacetylase inhibitors (HDACi), aryl hydrocarbon receptor (AHR) ligands, and inhibitors of cyclin-dependent kinases 8 and 19 (CDK8/19i), could enhance the stability and function of infused Tregs. (C) Genetic/epigenetic modification using CRISPR-based technologies could also promote Treg-specific expression programs and improve the safety and efficacy of Treg-based therapies. (D) Engineered IL-2 proteins and receptors can be used to improve the specificity of IL-2 therapy, thus extending Treg survival. IL-2 muteins harbor targeted mutations that limit binding to the dimeric IL-2 receptor, while preserving binding to the high-affinity trimeric IL-2 receptor in Tregs. Engineered orthogonal IL-2 protein only binds engineering-generated orthogonal IL-2R Tregs, thus allowing selective proliferation and survival of these cells. (E) Autologous Tregs are virally transduced to express a synthetic CAR or engineered TCR that could promote antigen specificity and trafficking after therapeutic infusion. Allogeneic Tregs are isolated from healthy people; to limit alloreactivity, genome-editing technologies could be used to remove endogenous TCRs and replace them with a synthetic TCR that confers increased specificity and potency.