Image_1_Alpha2beta1 Integrin (VLA-2) Protects Activated Human Effector T Cells From Methotrexate-Induced Apoptosis.TIF (238.18 kB)
Download file

Image_1_Alpha2beta1 Integrin (VLA-2) Protects Activated Human Effector T Cells From Methotrexate-Induced Apoptosis.TIF

Download (238.18 kB)
figure
posted on 15.10.2018, 15:01 by Amna Abderrazak, Mohammed-Amine El Azreq, Dalila Naci, Paul R. Fortin, Fawzi Aoudjit

β1 integrins are critical for T cell migration, survival and costimulation. The integrin α2β1, which is a receptor for collagen, also named VLA-2, is a major costimulatory pathway of effector T cells and has been implicated in arthritis pathogenesis. Herein, we have examined its ability to promote methotrexate (MTX) resistance by enhancing effector T cells survival. Our results show that attachment of anti-CD3-activated human polarized Th17 cells to collagen but not to fibronectin or laminin led to a significant reduction of MTX-induced apoptosis. The anti-CD3+collagen-rescued cells still produce significant amounts of IL-17 and IFNγ upon their reactivation indicating that their inflammatory nature is preserved. Mechanistically, we found that the prosurvival role of anti-CD3+collagen involves activation of the MTX transporter ABCC1 (ATP Binding Cassette subfamily C Member 1). Finally, the protective effect of collagen/α2β1 integrin on MTX-induced apoptosis also occurs in memory CD4+ T cells isolated from rheumatoid arthritis (RA) patients suggesting its clinical relevance. Together these results show that α2β1 integrin promotes MTX resistance of effector T cells, and suggest that it could contribute to the development of MTX resistance that is seen in RA.

History

References