They produce high levels of IFN-γ and tumor necrosis factor-α (TNF-α), and can kill infected cells through the release of granzymes and perforin into the immunological synapse . The cytokines IL-2 and IL-12 drive effector CTL differentiation by triggering STAT4 and STAT5 signaling, as well as through the phosphoinositide-3-kinase–Akt–mTOR and the rat sarcoma (RAS)-rat fibrosarcoma (RAF)–mitogen-activated protein kinase (MAPK) pathways . After resolution of infection, the bulk of CD8+ T cells die; however, a small Nutlin3a fraction remains as long-lived memory CD8+ T cells that respond to re-exposure to the cognate pathogen with strong proliferation and rapid conversion into
effector cells. Already at early stages of the response, phenotypic and functional markers help to distinguish between short-lived effector
CTLs and T cells that can give rise to long-lived memory cells. The CD44hiCD62Llokiller cell lectin-like receptor 1(KLRG1)hiIL7-Rαlo phenotype is characteristic for effector CTLs, whereas the memory precursors can be defined as CD44hiKLRG1loIL7-Rαhi. The differentiation of naïve CD8+ T cells into effector and memory CTLs is regulated by balanced expression of several transcription factors. Whereas BCL-6, Ibrutinib eomesodermin (EOMES), inhibitor of DNA-binding (ID) 3 and T-cell factor 1 (TCF1) are associated with memory cell differentiation and longevity, T-BET, ID2, and BLIMP-1 promote effector cell development . Like in Th17 cells, TGF-β Silibinin acts in combination with IL-6 or IL-21 to promote differentiation of IL-17-producing and ROR-γt-expressing Tc17 cells, which are detectable during viral infections, autoimmunity, and in tumor environments. Tc9-cell development parallels that of Th9 cells and is also induced by TGF-β and IL-4. These cells are detectable in the lamina propria of mice and in the periphery of mice and humans with atopy [62, 63]. In contrast
to CTLs, Tc9 and Tc17 cells display low cytotoxic activity [63-68]. Three recent studies demonstrated essential roles for IRF4 in effector CTL development. Although dispensable for initial activation and proliferation, IRF4 was required for CTL expansion, sustained expression of the effector CTL phenotype, and function. This was shown in three experimental models of infection with intracellular pathogens, namely in mice infected with lymphocytic choriomeningitis virus (LCMV), influenza virus, and L. monocytogenes [22, 23, 25]. Although WT mice can clear infection with L. monocytogenes within 10 days, Irf4–/– mice failed to clear the bacteria. This was caused by defective CD8+ T-cell function that was T-cell intrinsic, as transfer of WT CD8+ T cells into Irf4–/– mice rescued bacterial clearance . Furthermore, mice with conditional deletion of IRF4 in CD8+ T cells failed to control influenza infection . Similarly, defective CTL development in the absence of IRF4 was shown in response to infection with LCMV [22, 69].