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|Título:||Delta-like 1–mediated notch signaling enhances the in vitro conversion of human memory CD4 T cells into FOXP3-expressing regulatory T cells|
Pires, Ana R.
Victorino, Rui M. M.
Sousa, Ana E.
|Editora:||The American Association of Immunologists|
|Citação:||J Immunol 2014; 193:5854-5862|
|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-β 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.|
|Descrição:||© 2014 by The American Association of Immunologists, Inc.|
|Versão do Editor:||The definitive version is available at http://www.jimmunol.org/|
|Aparece nas colecções:||IMM - Artigos em Revistas Internacionais|
FM-LIC - Artigos em Revistas Internacionais
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