Delta-like 1-mediated Notch signaling enhances the in vitro conversion of human memory CD4 T cells into FOXP3-expressing regulatory T cells.

Autor:	Mota C; Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal; and Hospital Universitário de Santa Maria, Centro Hospitalar Lisboa Norte, 1649-035 Lisbon, Portugal., Nunes-Silva V; Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal; and., Pires AR; Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal; and., Matoso P; Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal; and., Victorino RM; Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal; and Hospital Universitário de Santa Maria, Centro Hospitalar Lisboa Norte, 1649-035 Lisbon, Portugal., Sousa AE; Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal; and., Caramalho I; Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal; and iriscaramalho@fm.ul.pt.
Jazyk:	angličtina
Zdroj:	Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2014 Dec 15; Vol. 193 (12), pp. 5854-62. Date of Electronic Publication: 2014 Nov 03.
DOI:	10.4049/jimmunol.1400198
Abstrakt:	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. (Copyright © 2014 by The American Association of Immunologists, Inc.)
Databáze:	MEDLINE
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