Identification of Noncytotoxic and IL-10–Producing CD8+AT2R+ T Cell Population in Response to Ischemic Heart Injury

Curato, Caterina; Slavić, Svetlana; Dong, Jun; Skorska, Anna; Altarche-Xifró, Wassim; Miteva, Kapka; Kaschina, Elena; Thiel, Andreas; Imboden, Hans; Wang, Jianan; Steckelings, Ulrike Muscha; Steinhoff, Gustav; Unger, Thomas; Li, Jun

doi:10.4049/jimmunol.0903681

Cited by 90 publications

(73 citation statements)

References 21 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). However, these autoreactive T cells can also be potentially deleterious (21).…”

supporting

confidence: 75%

Myocardial aging as a T-cell–mediated phenomenon

Ramos

Berg²,

Silva

et al. 2017

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

134

104

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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: 75%

Myocardial aging as a T-cell–mediated phenomenon

Ramos

Berg²,

Silva

et al. 2017

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

134

104

View full text Add to dashboard Cite

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“…In canine and mouse models of experimental infarction, IL-10 mRNA and protein expression is markedly upregulated, exhibiting a prolonged time course of expression (81,117). Subpopulations of T cells and macrophages are the cellular source of IL-10 in infarcted myocardial segments (69,117). In the canine model, IL-10 induction in the infarct is associated with attenuated expression of proinflammatory cytokines (117).…”

Section: Soluble Mediators As Negative Regulators Of the Postinfarctimentioning

confidence: 98%

Pathophysiology of Myocardial Infarction

Frangogiannis

2015

Comprehensive Physiology

465

360

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Myocardial infarction is defined as sudden ischemic death of myocardial tissue. In the clinical context, myocardial infarction is usually due to thrombotic occlusion of a coronary vessel caused by rupture of a vulnerable plaque. Ischemia induces profound metabolic and ionic perturbations in the affected myocardium and causes rapid depression of systolic function. Prolonged myocardial ischemia activates a "wavefront" of cardiomyocyte death that extends from the subendocardium to the subepicardium. Mitochondrial alterations are prominently involved in apoptosis and necrosis of cardiomyocytes in the infarcted heart. The adult mammalian heart has negligible regenerative capacity, thus the infarcted myocardium heals through formation of a scar. Infarct healing is dependent on an inflammatory cascade, triggered by alarmins released by dying cells. Clearance of dead cells and matrix debris by infiltrating phagocytes activates anti-inflammatory pathways leading to suppression of cytokine and chemokine signaling. Activation of the renin-angiotensin-aldosterone system and release of transforming growth factor-β induce conversion of fibroblasts into myofibroblasts, promoting deposition of extracellular matrix proteins. Infarct healing is intertwined with geometric remodeling of the chamber, characterized by dilation, hypertrophy of viable segments, and progressive dysfunction. This review manuscript describes the molecular signals and cellular effectors implicated in injury, repair, and remodeling of the infarcted heart, the mechanistic basis of the most common complications associated with myocardial infarction, and the pathophysiologic effects of established treatment strategies. Moreover, we discuss the implications of pathophysiological insights in design and implementation of new promising therapeutic approaches for patients with myocardial infarction.

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“…A subset of CD8 + T-cells that express angiotensin 2 receptor has been observed in the peri-infarct zone of rats 7 days after MI. 55 These CD8 + T-cells differ from cytotoxic angiotensin 2 receptor-negative CD8 + T-cells in their capacity to secrete IL-10 in response to angiotensin-II stimulation in vitro. Transferring these cells, harvested from a donor rat 7 days after MI, reduced infarct size 2 weeks after MI, thereby indicating CD8 + T-cells' potential significance in myocardial wound healing.…”

Section: T-cell Subsets Other Than Cd4 + T-cellsmentioning

confidence: 99%