IFN-α Subtypes Differentially Affect Human T Cell Motility

Abstract

The type I IFN family includes 14 closely related antiviral cytokines that are produced in response to viral infections. They bind to a common receptor, and have qualitatively similar biological activities. The physiological relevance of this redundancy is still unclear. In this study, we analyzed and compared the effects of two potent antiviral type I IFNs, IFN-α2 and IFN-α8, on the motility of various populations of human T lymphocytes in vitro. In this study, we show that IFN-α2 induces chemokinesis of both CD4+ and CD8+ T cells at various stages of differentiation, and induces functional changes that result in enhanced T cell motility, including up-regulation of the integrins LFA-1 and VLA-4, and subsequently, increased ICAM-1- and fibronectin-dependent migration. In contrast, IFN-α8 did not affect T cell motility, despite having similar antiviral properties and similar effects on the induction of the antiviral protein MxA. However, transcription of other IFN-stimulated genes showed that transcription of these genes is selectively activated by IFN-α2, but not IFN-α8, in T cells. Finally, while the antiviral activity of the two subtypes is inhibited by Abs against the two subunits of the IFN-α receptor, the chemokinetic effect of IFN-α2 is selectively blocked by Abs against the A1 receptor subunit. These observations are consistent with the possibility that subtype-specific intracellular signaling pathways are activated by type I IFNs in T lymphocytes.

Directed evolution of gene-shuffled IFN-α molecules with activity profiles tailored for treatment of chronic viral diseases

“…Previous studies performed with natural and hybrid human IFNs show significant variation in the ratios of various IFN-mediated activities including antiviral, antiproliferative, natural killer stimulatory, T cell stimulatory, T cell motility, and proliferation of primary B cells (1)(2)(3). These studies strongly suggest that there is in principle significant potential to modulate the ratios of the IFNmediated activities.…”

“…Although all type I IFNs are recognized by a single shared receptor comprised of two transmembrane subunits, IFNAR-1 and IFNAR-2, these cytokines have an unusually pleiotropic activity profile, including antiproliferative, antiviral, and immunomodulatory activities (1) and consequently this family of cytokines has found clinical application in cancer, chronic viral diseases, and autoimmune diseases (1)(2)(3).…”

Interferon-α and -β differentially regulate osteoclastogenesis: Role of differential induction of chemokine CXCL11 expression

“…For instance, CXCL10 is active in human umbilical vein endothelial cells in the absence of CXCR3 expression (37). It is remarkable that CXCL10 is precisely differentially induced by IFN-␣1 and IFN-␣2 or -␣21 in human T cells and dendritic cells (38), and that IFN-␣2 and -␣8 were shown to differentially affect T cell motility (39). These results suggest that differential activities between IFN subtypes acquire their biological relevance in the context of a cross-talk with the chemokine network to ultimately regulate ''chemokine-to-cytokine-to-chemokine'' cascades necessary for immune and developmental processes (40).…”

Type I IFN Contributes to NK Cell Homeostasis, Activation, and Antitumor Function

“…The IFNs were discovered and so named due to their ability to interfere with viral replication (10). Type I IFNs are pleiotropic cytokines that influence immune responses through the effects on myeloid cells (11,12), T cells (13,14), B cells (15), chemokinesis (16), and chemotaxis (17), as well as promote the acquisition of cytotoxic activity by both T and NK cells (18 -20).…”