Foxp3
            <sup>+</sup>
            CD4
            <sup>+</sup>
            T Cells Improve Healing After Myocardial Infarction by Modulating Monocyte/Macrophage Differentiation

Weirather, Johannes; Hofmann, Ulrich; Beyersdorf, Niklas; Ramos, Gustavo; Vogel, Benjamin; Frey, Anna; Ertl, Georg; Kerkau, Thomas; Frantz, Stefan

doi:10.1161/circresaha.115.303895

Cited by 572 publications

(542 citation statements)

References 61 publications

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“…During the last couple of years, our group demonstrated that ischemic, sterile myocardial injuries can elicit lymphocyte activation directed against cardiac antigens (13)(14)(15)(16). Our previous data, showing for the first time that CD4 + T cells reactive to cardiac components can foster the healing process that takes place after myocardial infarction, were corroborated by several other reports (13,15,(17)(18)(19)(20).…”

supporting

confidence: 74%

“…The mice were kept under light anesthesia with isoflurane [1.5% (vol/vol)], and short-axis two-dimensional echocardiographic images were acquired at the midpapillary and apical levels of the left ventricle (LV). End-diastolic and end-systolic diameters were measured from transversal M-mode tracings, according to standard protocols that were previously established in our laboratory (13,15). Only animals with a basal heart rate of >500 beats per minute (bpm) were included in the analysis.…”

Section: Methodsmentioning

confidence: 99%

“…A cell suspension of whole-heart samples was obtained after collagenase type-II digestion (1,000 IU/mL, 37°C, 30 min) and then ground in Hanks' balanced salt solution containing 1% (wt/vol) BSA (BSS/BSA) using a 40-μM cell strainer, according to previous descriptions (3,7,13,15). Lymph node samples were ground and prepared in BSS/BSA [5% (vol/vol) FCS].…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Myocardial aging as a T-cell–mediated phenomenon

Ramos

Berg²,

Silva

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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146

117

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In recent years, the myocardium has been rediscovered under the lenses of immunology, and lymphocytes have been implicated in the pathogenesis of cardiomyopathies with different etiologies. Aging is an important risk factor for heart diseases, and it also has impact on the immune system. Thus, we sought to determine whether immunological activity would influence myocardial structure and function in elderly mice. Morphological, functional, and molecular analyses revealed that the age-related myocardial impairment occurs in parallel with shifts in the composition of tissueresident leukocytes and with an accumulation of activated CD4 + Foxp3 − (forkhead box P3) IFN-γ + T cells in the heart-draining lymph nodes. A comprehensive characterization of different aged immune-deficient mouse strains revealed that T cells significantly contribute to age-related myocardial inflammation and functional decline. Upon adoptive cell transfer, the T cells isolated from the mediastinal lymph node (med-LN) of aged animals exhibited increased cardiotropism, compared with cells purified from young donors or from other irrelevant sites. Nevertheless, these cells caused rather mild effects on cardiac functionality, indicating that myocardial aging might stem from a combination of intrinsic and extrinsic (immunological) factors. Taken together, the data herein presented indicate that heart-directed immune responses may spontaneously arise in the elderly, even in the absence of a clear tissue damage or concomitant infection. These observations might shed new light on the emerging role of T cells in myocardial diseases, which primarily affect the elderly population.T he myocardial cellular composition has been revisited in recent years, and leukocyte subsets residing in the healthy heart have been described (1-10). Cardiac-resident macrophages exhibiting an M2-like gene expression profile were found to be distributed in close association with the coronary vascular bed (3), and niches for dendritic cells (CD11c + MHC-II high CD80/86 low ) were found near the cardiac valves of the intact heart (1). It was also demonstrated that cardiac-resident MHCII + cells process and present myosin heavy chain-alpha-derived peptides under steady-state conditions (11, 12) and prime T cells ex vivo (1). However, whether lymphocytes can seed the intact myocardium and whether T-cell priming with myocardial antigens can occur in the absence of an infection or autoimmune myocarditis remain elusive.More recently, accumulating evidence indicated that noninfectious myocardial diseases are modulated by T cells. During the last couple of years, our group demonstrated that ischemic, sterile myocardial injuries can elicit lymphocyte activation directed against cardiac antigens (13-16). Our previous data, showing for the first time that CD4 + T cells reactive to cardiac components can foster the healing process that takes place after myocardial infarction, were corroborated by several other reports (13,15,(17)(18)(19)(20). However, these autoreactive T cells can also b...

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supporting

confidence: 74%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Myocardial aging as a T-cell–mediated phenomenon

Ramos

Berg²,

Silva

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

146

117

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“…Platelets have been suggested to be an important source of TGF-β1 in the pressureoverloaded myocardium (29); however, their role as a source of growth factors in the infarcted myocardium has not been systematically investigated. Lymphocyte subsets and mast cells infiltrate the infarcted heart (30)(31)(32)(33) and are capable of producing TGF-βs. Moreover, much like most tissues, the normal myocardium may contain constitutive stores of matrix-bound latent TGF-β that can be activated following injury (34), initiating a response even in the absence of de novo synthesis.…”

Section: Regulation Of Tgf-β Isoforms In Myocardial Infarctionmentioning

confidence: 99%

“…TGF-β also serves as a central mediator in T lymphocyte differentiation and activation, critically regulating phenotype and function of all subpopulations (69)(70)(71). Although activated subsets of T lymphocytes have been implicated in repair and remodeling of the infarcted heart (30,32,72), the relative role of TGF-β signaling in their recruitment and activation has not been investigated.…”

Section: Tgf-βmentioning

confidence: 99%

The role of transforming growth factor (TGF)-β in the infarcted myocardium

Frangogiannis

2017

J. Thorac. Dis.

119

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The adult mammalian heart has negligible regenerative capacity. Following myocardial infarction, sudden necrosis of cardiomyocytes triggers an intense inflammatory reaction that clears the wound from dead cells and matrix debris, while activating a reparative program. A growing body of evidence suggests that members of the transforming growth factor (TGF)-β family critically regulate the inflammatory and reparative response following infarction. Although all three TGF-β isoforms (TGF-β1, -β2 and -β3) are markedly upregulated in the infarcted myocardium, information on isoform-specific actions is limited.Experimental studies have suggested that TGF-β exerts a wide range of actions on cardiomyocytes, fibroblasts, immune cells, and vascular cells. The findings are often conflicting, reflecting the contextdependence of TGF-β-mediated effects; conclusions are often based exclusively on in vitro studies and on associative evidence. TGF-β has been reported to modulate cardiomyocyte survival responses, promote monocyte recruitment, inhibit macrophage pro-inflammatory gene expression, suppress adhesion molecule synthesis by endothelial cells, promote myofibroblast conversion and extracellular matrix synthesis, and mediate both angiogenic and angiostatic effects. This review manuscript discusses our understanding of the cell biological effects of TGF-β in myocardial infarction. We discuss the relative significance of downstream TGF-β-mediated Smad-dependent and -independent pathways, and the risks and challenges of therapeutic TGF-β targeting. Considering the high significance of TGF-β-mediated actions in vivo, study of cell-specific effects and dissection of downstream signaling pathways are needed in order to design safe and effective therapeutic approaches.

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