Abstract
Improper regulation of B cell responses leads to excessive production of antibodies and contributes to the development of autoimmune disease. T helper 17 (Th17) cells also drive the development of autoimmune disease, but the role of B cells in shaping Th17 cell-mediated immune responses, as well as the reciprocal regulation of B cell responses by IL-17 family cytokines, remains unclear. The aim of this study was to characterize the regulation of IL-17A and IL-17F in a model of T cell-dependent B cell activation. Stimulation of primary human B cell and peripheral blood mononuclear cell (BT) co-cultures with α-IgM and a non-mitogenic concentration of superantigens for three days promoted a Th17 cell response as evidenced by increased expression of Th17-related gene transcripts, including Il17f, Il21, Il22, and Il23r, in CD4 T cells, as well as the secretion of IL-17A and IL-17F protein. We tested the ability of 144 pharmacologic modulators representing 91 different targets or pathways to regulate IL-17A and IL-17F production in these stimulated BT co-cultures. IL-17A production was found to be preferentially sensitive to inhibition of the PI3K/mTOR pathway, while prostaglandin EP receptor agonists, including PGE2, increased IL-17A concentrations. In contrast, the production of IL-17F was inhibited by PGE2, but selectively increased by TLR2 and TLR5 agonists. These results indicate that IL-17A regulation is distinct from IL-17F in stimulated BT co-cultures and that this co-culture approach can be used to identify pathway mechanisms and novel agents that selectively inhibit production of IL-17A or IL-17F.
Highlights
Activation of T and B cells by cognate interactions is critical for adaptive immune responses, but improper regulation of this process can drive the development of autoimmune disease
We have previously described a co-culture assay with primary human B cells and peripheral blood mononuclear cells (PBMC) stimulated with a-IgM and a relatively low concentration (0.02 ng/ml) of the SEB and TSST-1 superantigens (SAg) that models T cell-dependent B cell activation (BT BioMAP system) [12]
We report that regulation of IL-17A occurs through pathways distinct from those that regulate IL-17F in a primary human cell-based model of T cell-dependent B cell activation (BioMAPH BT system)
Summary
Activation of T and B cells by cognate interactions is critical for adaptive immune responses, but improper regulation of this process can drive the development of autoimmune disease. B cell activation is triggered by BCR-mediated binding of antigen in secondary lymphoid structures, where B cells present antigenderived peptides on HLA proteins and interact with cognate T cells [1]. This interaction, in conjunction with the engagement of CD40 on B cells by CD40L on T cells, results in B cell proliferation, class switching and somatic hypermutation of antibody genes, and formation of memory B cell populations. Th17 cells, a CD4 T helper subset characterized by the production of IL-17A, IL-17F, IL-21, and IL-22 cytokines, are implicated in the pathogenesis of many autoimmune diseases [2]. Th17 cells influence GC formation and B cell function, the role of B cells in influencing Th17 responses remains to be defined
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