IL-21 Up-Regulates the Expression of Genes Associated with Innate Immunity and Th1 Response

Abstract

IL-21 is a recently characterized T cell-derived cytokine that regulates NK and T cell function. IL-21R shares the common γ-chain (γc) with the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15. Despite the same γc, these cytokines have different effects on diverse cells. In this study, we have studied IL-15- and IL-21-induced gene expression in human primary NK and T cells and the NK-92 cell line. Both IL-15 and IL-21 rapidly induced mRNA synthesis for IFN-γ, T-bet, IL-2Rα, IL-12Rβ2, IL-18R, and myeloid differentiation factor 88 (MyD88), the genes that are important in activating innate immunity and Th1 response. IL-15 induced STAT5 DNA binding to the IL-2Rα IFN-γ-activated sequence (GAS), MyD88 GAS, and c-sis-inducible elements, whereas IL-21 induced STAT3 DNA binding to MyD88 GAS and c-sis-inducible elements. IL-21-induced STAT3 activation was verified by immunoprecipitation and Western blotting with anti-phosphotyrosine Ab. In addition, pretreatment of NK-92 cells with IL-15 or IL-21 strongly enhanced IL-12-induced STAT4 DNA binding to IL-2Rα GAS. The induction of IFN-γ, T-bet, IL-12Rβ2, and IL-18R gene expression in NK cells, along with STAT3 activation, suggests that IL-21 is involved in the activation of innate immune responses. Moreover, the enhanced transcription of these genes in T cells establishes a significant role for IL-21 also in the Th1 response.

Transcriptional control of human T‐BET expression: The role of Sp1

“…Work regarding the regulation of the T-bet gene itself has been limited; we know it is positively regulated by the Notch1 transcription factor and by proinflammatory cytokines such as IL-12, IL-15 and IL-18 [1,3,4,14,15] and IFN-c [17], and negatively regulated by TGF-b [14,15,20]. Studies of the transcription factors activated by these cytokines suggest that STAT4-, STAT1-and SMADdependent and -independent mechanisms are likely involved in the regulation of T-bet [5,8,[14][15][16][18][19][20][21], but definitive characterizations of these and other potential regulatory pathways have not been reported.…”

“…T-bet T-box expressed in T cells is a member of the T-box transcription factor family and has been shown to be (i) a positive "master" transcriptional regulator of IFN-c production in CD4 + T cells, NK cells, and effector CD8 + T cells [1][2][3][4] and, (ii) important for the commitment of CD4 + T cells to Th1 development [3,[5][6][7]. T-bet has also recently been shown to regulate murine IFN-c production by B effector 1 cells [8].…”

“…Data from mice and humans suggest that monocyte-derived proinflammatory cytokines IL-12, IL-15 and IL-18 each activate various signal transducers and activators of transcription (STAT) and are also able to induce transcription of T-bet and its human homologue T-BET [1,3,4,14,15]. This suggests that STAT may play a role in the regulation of this gene; however, the regulation of T-bet has been reported as both STAT4 dependent and STAT4 independent [5,7,16].…”

IL-21 Promotes Differentiation of Naive CD8 T Cells to a Unique Effector Phenotype

“…Alternatively or additionally, it is possible, given our data, that IL-21 production by activated CD4 T cells could play a role in down-modulating IFN-␥ secretion by CD8 T cells at the site of secondary challenge with Ag. Evidence exists to indicate that both Th1 and Th2 cells can produce IL-21 (35,(55)(56)(57). Because activated CD4 Th1 cells are already secreting copious quantities of IFN-␥, this may provide a mechanism for the avoidance of cytokine storm repercussions.…”

NK Cells and Cancer

“…The induction of type I immune responses, as well as the terminal differentiation of NK cells, therefore appear relevant to an effective antitumor activity. To this regard, IL-21, a promising cytokine able to build up NK cell antitumor activity (59), has been found to promote both the expression of genes associated with type I response and the terminal differentiation of the highly cytotoxic CD56 dim / CD16 ϩ NK cell subset, which can potentially direct ADCC against tumor cells via CD16-Fc ligation (18,19,60). NK cellmediated ADCC response against tumor targets can be promoted by administration of mAbs to tumor-associated Ags (61, 62) (Fig.…”