Project description:Long recognized to be potent suppressors of immune responses, Foxp3(+)CD4(+) regulatory T (Treg) cells are being rediscovered as regulators of nonimmunological processes. We describe a phenotypically and functionally distinct population of Treg cells that rapidly accumulated in the acutely injured skeletal muscle of mice, just as invading myeloid-lineage cells switched from a proinflammatory to a proregenerative state. A Treg population of similar phenotype accumulated in muscles of genetically dystrophic mice. Punctual depletion of Treg cells during the repair process prolonged the proinflammatory infiltrate and impaired muscle repair, while treatments that increased or decreased Treg activities diminished or enhanced (respectively) muscle damage in a dystrophy model. Muscle Treg cells expressed the growth factor Amphiregulin, which acted directly on muscle satellite cells in vitro and improved muscle repair in vivo. Thus, Treg cells and their products may provide new therapeutic opportunities for wound repair and muscular dystrophies.
Project description:Acute respiratory distress syndrome (ARDS) causes significant morbidity and mortality each year. There is a paucity of information regarding the mechanisms necessary for ARDS resolution. Foxp3(+) regulatory T cells (Foxp3(+) T(reg) cells) have been shown to be an important determinant of resolution in an experimental model of lung injury. We demonstrate that intratracheal delivery of endotoxin (lipopolysaccharide) elicits alveolar epithelial damage from which the epithelium undergoes proliferation and repair. Epithelial proliferation coincided with an increase in Foxp3(+) T(reg) cells in the lung during the course of resolution. To dissect the role that Foxp3(+) T(reg) cells exert on epithelial proliferation, we depleted Foxp3(+) T(reg) cells, which led to decreased alveolar epithelial proliferation and delayed lung injury recovery. Furthermore, antibody-mediated blockade of CD103, an integrin, which binds to epithelial expressed E-cadherin decreased Foxp3(+) T(reg) numbers and decreased rates of epithelial proliferation after injury. In a non-inflammatory model of regenerative alveologenesis, left lung pneumonectomy, we found that Foxp3(+) T(reg) cells enhanced epithelial proliferation. Moreover, Foxp3(+) T(reg) cells co-cultured with primary type II alveolar cells (AT2) directly increased AT2 cell proliferation in a CD103-dependent manner. These studies provide evidence of a new and integral role for Foxp3(+) T(reg) cells in repair of the lung epithelium.
Project description:Skeletal muscle repair and regeneration after injury is a multi-stage process, involving a dynamic inflammatory microenvironment consisting of a complex network formed by the interaction of immune cells and their secreted cytokines. The homeostasis of the inflammatory microenvironment determines whether skeletal muscle repair tissues will ultimately form scar tissue or regenerative tissue. Regulatory T cells (Tregs) regulate homeostasis within the immune system and self-immune tolerance, and play a crucial role in skeletal muscle repair and regeneration. Dysregulated Tregs function leads to abnormal repair. In this review, we discuss the role and mechanisms of Tregs in skeletal muscle repair and regeneration after injury and provide new strategies for Treg immunotherapy in skeletal muscle diseases.
Project description:Lung transplantation represents an option for patients with a variety of end-stage lung diseases. While surgical advances have led to improvements in short-term survival, long-term survival is limited by chronic rejection termed bronchiolitis obliterans syndrome (BOS). A growing body of work is devoted to determining why some patients develop BOS. One avenue of interest that has emerged recently is the role that regulatory T cells (Tregs) may have in protection from BOS. In this review, we will discuss the evidence that Tregs are relevant to outcomes following transplant. We will discuss the relevant animal models, in vitro assays, and human observational studies that support a role for Tregs. We will also explore the interplay between injurious T cells such as Th17 cells and Tregs as well as the effect that additional cell types and chemokines have on the balance between inflammation and regulation. Finally, we will review emerging therapies which may harness the ability of Tregs to lessen the effects of BOS.
Project description:Accumulating evidence has demonstrated that immune cells play an important role in the regulation of tissue repair and regeneration. After injury, danger signals released by the damaged tissue trigger the initial pro-inflammatory phase essential for removing pathogens or cellular debris that is later replaced by the anti-inflammatory phase responsible for tissue healing. On the other hand, impaired immune regulation can lead to excessive scarring and fibrosis that could be detrimental for the restoration of organ function. Regulatory T-cells (Treg) have been revealed as the master regulator of the immune system that have both the immune and regenerative functions. In this review, we will summarize their immune role in the induction and maintenance of self-tolerance; as well as their regenerative role in directing tissue specific response for repair and regeneration. The latter is clearly demonstrated when Treg enhance the differentiation of stem or progenitor cells such as satellite cells to replace the damaged skeletal muscle, as well as the proliferation of parenchymal cells including neonatal cardiomyocytes for functional regeneration. Moreover, we will also discuss the reparative and regenerative role of Treg with a particular focus on blood vessels and cardiac tissues. Last but not least, we will describe the ongoing clinical trials with Treg in the treatment of autoimmune diseases that could give clinically relevant insights into the development of Treg therapy targeting tissue repair and regeneration.
Project description:Repair of injured lungs represents a longstanding therapeutic challenge. We recently demonstrated that human and mouse embryonic lung tissue from the canalicular stage of development are enriched with lung progenitors, and that a single cell suspension of canalicular lungs can be used for transplantation, provided that lung progenitor niches in the recipient mice are vacated by strategies similar to those used in bone marrow transplantation. Considering the ethical limitations associated with the use of fetal cells, we investigated here whether adult lungs could offer an alternative source of lung progenitors for transplantation. We show that intravenous infusion of a single cell suspension of adult mouse lungs from GFP+ donors, following conditioning of recipient mice with naphthalene and subsequent sublethal irradiation, led to marked colonization of the recipient lungs, at 6-8 weeks post-transplant, with donor derived structures including epithelial, endothelial, and mesenchymal cells. Epithelial cells within these donor-derived colonies expressed markers of functionally distinct lung cell types, and lung function, which is significantly compromised in mice treated with naphthalene and radiation, was found to be corrected following transplantation. Dose response analysis suggests that the frequency of patch forming cells in adult lungs was about threefold lower compared to that found in E16 fetal lungs. However, as adult lungs are much larger, the total number of patch forming cells that can be collected from this source is significantly greater. Our study provides proof of concept for lung regeneration by adult lung cells after preconditioning to vacate the pulmonary niche. Stem Cells Translational Medicine 2018;7:68-77.
Project description:Synthetic lethality is an efficient mechanism-based approach to selectively target DNA repair defects. Excision repair cross-complementation group 1 (ERCC1) deficiency is frequently found in non-small-cell lung cancer (NSCLC), making this DNA repair protein an attractive target for exploiting synthetic lethal approaches in the disease. Using unbiased proteomic and metabolic high-throughput profiling on a unique in-house-generated isogenic model of ERCC1 deficiency, we found marked metabolic rewiring of ERCC1-deficient populations, including decreased levels of the metabolite NAD+ and reduced expression of the rate-limiting NAD+ biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT). We also found reduced NAMPT expression in NSCLC samples with low levels of ERCC1. These metabolic alterations were a primary effect of ERCC1 deficiency, and caused selective exquisite sensitivity to small-molecule NAMPT inhibitors, both in vitro - ERCC1-deficient cells being approximately 1,000 times more sensitive than ERCC1-WT cells - and in vivo. Using transmission electronic microscopy and functional metabolic studies, we found that ERCC1-deficient cells harbor mitochondrial defects. We propose a model where NAD+ acts as a regulator of ERCC1-deficient NSCLC cell fitness. These findings open therapeutic opportunities that exploit a yet-undescribed nuclear-mitochondrial synthetic lethal relationship in NSCLC models, and highlight the potential for targeting DNA repair/metabolic crosstalks for cancer therapy.
Project description:A cardinal feature of COVID-19 is lung inflammation and respiratory failure. In a prospective multi-country cohort of COVID-19 patients, we found that increased Notch4 expression on circulating regulatory T (Treg) cells was associated with disease severity, predicted mortality, and declined upon recovery. Deletion of Notch4 in Treg cells or therapy with anti-Notch4 antibodies in conventional and humanized mice normalized the dysregulated innate immunity and rescued disease morbidity and mortality induced by a synthetic analog of viral RNA or by influenza H1N1 virus. Mechanistically, Notch4 suppressed the induction by interleukin-18 of amphiregulin, a cytokine necessary for tissue repair. Protection by Notch4 inhibition was recapitulated by therapy with Amphiregulin and, reciprocally, abrogated by its antagonism. Amphiregulin declined in COVID-19 subjects as a function of disease severity and Notch4 expression. Thus, Notch4 expression on Treg cells dynamically restrains amphiregulin-dependent tissue repair to promote severe lung inflammation, with therapeutic implications for COVID-19 and related infections.
Project description:Murine regulatory T (Treg) cells in tissues promote tissue homeostasis and regeneration. We sought to identify features that characterize human Treg cells with these functions in healthy tissues. Single-cell chromatin accessibility profiles of murine and human tissue Treg cells defined a conserved, microbiota-independent tissue-repair Treg signature with a prevailing footprint of the transcription factor BATF. This signature, combined with gene expression profiling and TCR fate mapping, identified a population of tissue-like Treg cells in human peripheral blood that expressed BATF, chemokine receptor CCR8 and HLA-DR. Human BATF+CCR8+ Treg cells from normal skin and adipose tissue shared features with nonlymphoid T follicular helper-like (Tfh-like) cells, and induction of a Tfh-like differentiation program in naive human Treg cells partially recapitulated tissue Treg regenerative characteristics, including wound healing potential. Human BATF+CCR8+ Treg cells from healthy tissue share features with tumor-resident Treg cells, highlighting the importance of understanding the context-specific functions of these cells.