Alpha2beta1 Integrin (VLA-2) Protects Activated Human Effector T Cells From Methotrexate-Induced Apoptosis.

ABSTRACT: ?1 integrins are critical for T cell migration, survival and costimulation. The integrin ?2?1, 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 IFN? 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/?2?1 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 ?2?1 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.

SUBMITTER: Abderrazak A 

PROVIDER: S-EPMC6197073 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature