| IL-21 is a recently described member of the gammac chain family of cytokines that has pleiotropic effects on the proliferation, differentiation, and effector functions of its target cells. While IL-21 is selectively expressed by Th2 cells, the IL-21R is widely expressed across the immune system on B, T, NK and dendritic cells. At present, the role IL-21 plays in regulating the immune response is controversial given that it has been described both as an inhibitory and a stimulatory cytokine.; The first part of this thesis investigates the molecular basis of the Th2 cell-specific expression of IL-21. It was found that the proximal IL-21 promoter controls the Th cell subset-specific expression of IL-21 through the action of two transcription factors, NFATc2 and T-bet. While NFATc2 directly binds to and activates transcription of the IL-21 promoter in Th2 cells, T-bet represses its transcription by inhibiting the binding of NFATc2 to the promoter in Th1 cells. These findings suggest a novel model for the transcriptional regulation of Th cell subset-specific genes.; Next, given that IL-21 is a Th2 cytokine whose receptor is highly expressed on B cells, the effects of IL-21 on B cells were examined. IL-21 was demonstrated to directly induce the apoptosis of primary murine B cells via down-regulation of the anti-apoptotic factors Bcl-2 and Bcl-xL, a novel function for a gamma c chain cytokine. Furthermore, activation of primary B cells with survival stimuli such as IL-4, LPS, or anti-CD40 does not prevent IL-21-mediated apoptosis. However, B cells stimulated with IL-21 in the context of both proper antigen receptor activation and co-stimulation are no longer susceptible to IL-21-mediated apoptosis. Instead, IL-21 promotes their development into antibody-secreting plasma cells. In fact, the IL-21R -/- mouse is severely impaired in generating antigen-specific B cell responses upon immunization.; Overall, the data presented in this thesis suggest that IL-21 is a critical component of the Th2-driven humoral response in that it promotes antigen-specific B cell responses while possibly inhibiting the expansion of inappropriately or "bystander" activated B cells through the induction of an apoptotic pathway. |
