Abstract
The cytokine IL-21 is a potent immune modulator with diverse mechanisms of action on multiple cell types. IL-21 is in clinical use to promote tumor rejection and is an emerging target for neutralization in the setting of autoimmunity. Despite its clinical potential, the biological actions of IL-21 are not yet fully understood and the full range of effects of this pleiotropic cytokine are still being uncovered. In this study, we identify a novel role for IL-21 as an inducer of the costimulatory ligand CD86 on B lymphocytes. CD86 provides critical signals through T cell–expressed CD28 that promote T cell activation in response to Ag engagement. Expression levels of CD86 are tightly regulated in vivo, being actively decreased by regulatory T cells and increased in response to pathogen-derived signals. In this study, we demonstrate that IL-21 can trigger potent and sustained CD86 upregulation through a STAT3 and PI3K-dependent mechanism. We show that elevated CD86 expression has functional consequences for the magnitude of CD4 T cell responses both in vitro and in vivo. These data pinpoint CD86 upregulation as an additional mechanism by which IL-21 can elicit immunomodulatory effects.
Highlights
We demonstrate that IL-21 can trigger potent and sustained CD86 upregulation through a STAT3 and PI3K-dependent mechanism
To explore the influence of IL-21 on costimulatory ligand expression, murine splenocytes were cultured in the presence or absence of IL-21 for 16 h and the expression of CD86 and CD80 was assessed by flow cytometry
IL-21 has a well-established role in the induction of plasma cell differentiation [10, 11] and this involves the cooperative binding of STAT3 and IFN regulatory factor 4 to the IL-21 response element in the Prdm1 gene encoding Blimp-1 [34]
Summary
In this study we identify a novel role for IL-21 in upregulating the expression of the costimulatory ligand CD86 on B cells. These data suggest an additional mechanism by which IL-21 may augment adaptive immune responses and reveal a further level of T cell/B cell interaction directed by this cytokine. The ability of IL-21 to upregulate B cell CD86 expression was completely abrogated in the presence of cycloheximide, indicating a requirement for protein neosynthesis (Fig. 2B, 2C).
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