Diverse Immunomodulatory Effects of Individual IFNα Subtypes on Virus-Specific CD8+ T Cell Responses

Clinical administration of Interferon alpha (IFN alpha) resulted in limited therapeutic success against some viral infections. Immune modulation of CD8(+) T cell responses during IFN alpha therapy is believed to play a pivotal role in promoting viral clearance. However, these clinical studies primarily focused on IFN alpha subtype 2. To date, the immunomodulatory roles of the remaining 10-13 IFN alpha subtypes remains poorly understood, thereby precluding assessments of their potential for more effective treatments. Here, we report that virus-specific CD8(+) T cell responses were influenced to various extents by individual IFN alpha subtypes. IFN alpha 4, 6, and 9 had the strongest effects on CD8(+) T cells, including antiproliferative effects, improved cytokine production and cytotoxicity. Interestingly, augmented cytokine responses were dependent on IFN alpha subtype stimulation of dendritic cells (DCs), while antiproliferative effects and cytotoxicity were mediated by IFNAR signaling in either CD8(+) T cells or DCs. Thus, precise modulation of virus-specific CD8(+) T cell responses may be feasible for specific antiviral immunotherapies through careful selection and administration of individual IFN alpha subtypes.