Alpha2beta1 integrin signaling augments T cell receptor-dependent production of interferon-gamma in human T cells

The mechanisms by which β1 integrins modulate T cell costimulation are still poorly defined. In this study, we examined the role of collagen-binding integrins α1β1 and α2β1 in the regulation of interferon-γ (IFN-γ). We demonstrated that ligation of α2β1 integrin with Collagen type I (Coll I) but not α1β1 integrin with Collagen IV (Coll IV) significantly augmented T cell receptor (TCR)-dependent expression and production of IFN-γ by effector T cells. The effect of Coll I was not due to cell adhesion as soluble Coll I also augmented TCR-dependent production of IFN-γ. Inhibition studies indicated that activation of ERK and JNK MAPKs and PI3K/AKT are necessary for both TCR- and TCR + α2β1 integrin-dependent IFN-γ production and that Coll I increases TCR-dependent activation of ERK and JNK MAPKs, and AKT. In addition, our results showed that Coll IV is less potent than Coll I in augmenting TCR-dependent activation of JNK/MAPK, which may explain the differential effect of collagen matrices on TCR-dependent IFN-γ production. Together, these results indicate that the costimulatory effect of Coll I on IFN-γ expression is integrated at the levels of ERK and JNK MAPKs and PI3K/AKT signaling pathways and suggest JNK/MAPK as a major signaling pathway of Coll I costimulation. Thus, our study identifies α2β1 integrin as an important regulatory pathway of IFN-γ expression and provides novel insights into the signaling mechanisms of integrin costimulation in T cells. As such, this study further supports the functional importance that Coll I interactions may have on the control of T cell-dependent Th1 inflammatory diseases.