Abstract In patients with HIV infection, reconstitution of the CD4 T cell pool after initiation of combination antiretroviral therapy (cART) is a slow process and depends on CD4 T cell counts prior to therapy. This suggests that the CD4 T cell pool is under homeostatic pressure compared to the CD8 T cell pool which is expanded. We have previously shown that lymphopenia and IL-7 increase expression of the Signal Transducer and Activator of Transcriptions 1, 2 and 3 (STAT1, 2 and 3) leading to an enhanced response to Type I IFNs and contributing to the immune activation of CD4 T cells. A recent report has shown that IL-27, a member of the IL-12 family of cytokines, inhibits HIV replication in monocytes and monocyte-derived dendritic cells. IL-27 signals through the JAK/STAT and MAPK pathways. Since IL-27 activates STAT1 and STAT3, we hypothesized that IL-7-dependent modulation of STATs expression can influence the response to IL-27 in T cells from HIV patients. We tested whether the γc-cytokines IL-2, IL-7, IL-15 have an effect on STATs expression and their impact on IL-27 signaling in T cells from healthy controls. We found that in addition to IL-7, IL-2 and IL-15 significantly increased expression of STAT1 and STAT3 in CD4 and CD8 T cells and led to an enhanced STAT1 and STAT3 activation upon IL-27 in vitro stimulation. We also found that compared to healthy controls, CD4 T cells from HIV infected patients had a significantly increased STAT1 expression and showed enhanced STAT1 activation upon in vitro stimulation with IL-27. This effect was not observed in CD8 T cells. These data suggest that IL-2, IL-7 and IL-15 modulate IL-27 signaling. In the context of HIV infection, the enhanced IL-27-dependent STAT1 activation may impact CD4 T cell activation and function.