proteins also lead to the activation of phosphatidylinositol 3-kinase (PI3K). PI3K leads to the activation of protein kinase C-δ (PKC-δ) which phosphorylates the amino acid serine in STAT1 transcription factors. The phosphorylation of the serine in STAT1-STAT1 homodimers are essential for the full transcription process to occur. Other signaling pathways Other signaling pathways that are triggered by IFN-γ are the mTOR signaling pathway, the MAPK signaling pathway, and the PI3K/AKT signaling pathway. Biological activity IFN-γ is secreted by T helper cells (specifically, Th1 cells), cytotoxic T cells (TC cells), macrophages, mucosal epithelial cells and NK cells. IFN-γ is both an important autocrine signal for professional APCs in early innate immune response, and an important paracrine signal in adaptive immune response. The expression of IFN-γ is induced by the cytokines IL-12, IL-15, IL-18, and type I IFN. IFN-γ is the only Type II interferon and it is serologically distinct from Type I interferons; it is acid-labile, while the type I variants are acid-stable. IFN-γ has antiviral, immunoregulatory, and anti-tumor properties. It alters transcription in up to 30 genes producing a variety of physiological and cellular responses. Among the effects are: Promotes NK cell activity Increases antigen presentation and lysosome activity of macrophages. Activates inducible nitric oxide synthase (iNOS) Induces the production of IgG2a and IgG3 from activated plasma B cells Causes normal cells to increase expression of class I MHC molecules as well as class II MHC on antigen-presenting cells—to be specific, through induction of antigen processing genes, including subunits of the immunoproteasome (MECL1, LMP2, LMP7), as well as TAP and ERAAP in addition possibly to the direct upregulation of MHC heavy chains and B2-microglobulin itself Promotes adhesion and binding required for leukocyte migration Induces the expression of intrinsic defense factors—for example, with respect to retroviruses, relevant genes include TRIM5alpha, APOBEC, and Tetherin, representing directly antiviral effects Primes alveolar macrophages against secondary bacterial infections. IFN-γ is the primary cytokine that defines Th1 cells: Th1 cells secrete IFN-γ, which in turn causes more undifferentiated CD4+ cells (Th0 cells) to differentiate into Th1 cells , representing a positive feedback loop—while suppressing Th2 cell differentiation. (Equivalent defining cytokines for other cells include IL-4 for Th2 cells and IL-17 for Th17 cells.) NK cells and CD8+ cytotoxic T cells also produce IFN-γ. IFN-γ suppresses osteoclast formation by rapidly degrading the RANK adaptor protein TRAF6 in the RANK-RANKL signaling pathway, which otherwise stimulates the production of