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1.
Adv Exp Med Biol ; 1003: 225-250, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28667561

RESUMO

The adult mammalian heart displays negligible regenerative capacity. Therefore, myocardial infarction (MI) often results in an irreversible loss of contractile tissue, leading to a collagenous scar formation, progressive remodelling and heart failure (HF). Over the past few years, emerging evidences indicate that a myocardial ischemic injury mobilizes not only sterile unspecific inflammation but also lymphocyte-mediated immune responses to cardiac auto-antigens. In the current chapter, we depict the infarcted heart as a "wounded" tissue and focus on the dynamic events leading to myocardial repair, with special emphasis on the role played by lymphocytes in this process.


Assuntos
Linfócitos B/imunologia , Infarto do Miocárdio/imunologia , Miocárdio/imunologia , Regeneração , Linfócitos T/imunologia , Cicatrização , Animais , Autoanticorpos/imunologia , Autoanticorpos/metabolismo , Linfócitos B/metabolismo , Linfócitos B/patologia , Humanos , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Fenótipo , Transdução de Sinais , Linfócitos T/metabolismo , Linfócitos T/patologia
2.
Proc Natl Acad Sci U S A ; 114(12): E2420-E2429, 2017 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-28255084

RESUMO

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 tissue-resident 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.


Assuntos
Envelhecimento/imunologia , Linfócitos T CD4-Positivos/imunologia , Miocárdio/imunologia , Transferência Adotiva , Animais , Coração/crescimento & desenvolvimento , Humanos , Linfonodos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
3.
J Autoimmun ; 56: 98-110, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25481744

RESUMO

Thymus-derived FOXP3-expressing regulatory T-cells (tTregs) are master orchestrators of physiological and pathological immune responses, thus constituting ideal targets for the treatment of autoimmunity. Despite their clinical importance, the developmental program governing their differentiation in the human thymus remains poorly understood. Here, we investigated the role of common gamma-chain cytokines in human tTreg differentiation, by performing gain- and loss-of-function experiments in 3D and 2D postnatal thymic cultures. We identified IL-2 and IL-15 as key molecular determinants in this process and excluded a major function for IL-4, IL-7 and IL-21. Mechanistically, IL-2 and IL-15 were equally able to drive tTreg precursor differentiation into FOXP3(+) cells, and promote tTreg proliferation and survival. Both cytokines also increased the expression levels of molecules associated with effector function within FOXP3(+) subsets, supporting their involvement in tTreg functional maturation. Furthermore, we revealed that IL-2 and IL-15 are expressed in a non-overlapping pattern in the human thymus, with the former produced mainly by mature αß and γδ thymocytes and the latter by monocyte/macrophages and B lymphocytes. Our results identify core mechanisms dictating human tTreg development, with IL-2 and IL-15 defining specific niches required for tTreg lineage stabilization and differentiation, with implications for their therapeutic targeting in autoimmune conditions.


Assuntos
Expressão Gênica , Interleucina-15/genética , Interleucina-2/genética , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Timo/imunologia , Timo/metabolismo , Diferenciação Celular/imunologia , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Citocinas/genética , Citocinas/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Humanos , Imunofenotipagem , Interleucina-15/metabolismo , Interleucina-2/metabolismo , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Fenótipo , Transdução de Sinais , Linfócitos T Reguladores/citologia , Timócitos/citologia , Timócitos/imunologia , Timócitos/metabolismo
4.
J Immunol ; 193(12): 5854-62, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-25367118

RESUMO

FOXP3-expressing regulatory T cells (Treg) are essential for the prevention of autoimmunity and were shown to be reduced and/or dysfunctional in several autoimmune diseases. Although Treg-based adoptive transfer represents a promising therapy, the large cell number required to achieve clinical efficacy constitutes an important limitation. Therefore, novel strategies to generate bona fide in vitro-induced Treg (iTreg) are critical. In this study, we report that human memory CD4 T cells can be efficiently converted into iTreg, and that Delta-like 1 (DL1)-mediated Notch signaling significantly enhances this process. The iTreg generated in the presence of DL1 featured higher levels of Treg function-associated molecules and were efficient suppressors. Importantly, these iTreg displayed a stable phenotype in long-term cultures, even in the presence of proinflammatory cytokines. Additionally, DL1 potentiated FOXP3 acquisition by memory CD4 cells through the modulation of the TGF-ß signaling pathway and of Foxp3 transcription. Our data demonstrate that iTreg can be efficiently induced from memory CD4 cells, a subset enriched in relevant specificities for targeting in autoimmune diseases, and that DL1 enhances this process. DL1 also enhanced the proliferation and Treg function-associated marker expression of ex vivo-stimulated human circulating FOXP3(+) cells. Manipulation of the Notch signaling pathway constitutes a promising approach to boost the in vitro generation of iTreg and ex vivo Treg expansion, thus facilitating the establishment of effective Treg-based adoptive therapy in autoimmune diseases.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Memória Imunológica , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas de Membrana/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Antígenos de Superfície/metabolismo , Proteínas de Ligação ao Cálcio , Reprogramação Celular/imunologia , Fatores de Transcrição Forkhead/metabolismo , Humanos , Imunofenotipagem , Fenótipo
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