The Active Metabolite Of Spleen Tyrosine Kinase Inhibitor Fostamatinib Abrogates The Cd4(+) T Cell-Priming Capacity Of Dendritic Cells

Methods. Antigen-specific in vivo systems and in vitro fluorescence microscopy were combined to investigate the effects of fostamatinib on antigen-specific interactions between dendritic cells (DCs) and CD4(+) T cells.Results. Although it has previously been shown that R406 reduces the response of DCs to immune complexes (ICs), we found that fostamatinib failed to reduce specific CD4(+) T cell proliferation in mice after immunization with ICs. However, we observed in vitro that R406 reduces both the area and duration of cellular interactions between IC-activated DCs and specific CD4(+) T cells during the initial phase of cellular crosstalk. This led to diminished proliferation of antigen-specific CD4(+) T cells after R406 treatment compared with vehicle controls. This decreased proliferative capacity of CD4(+) T cells was accompanied by reduced expression of the co-stimulatory molecules, inducible T cell co-stimulator (ICOS) and PD-1, and abrogation of the production of inflammatory cytokines such as IFN-gamma and IL-17.Conclusion. Our findings indicate a potential mechanism by which this compound may be effective in inhibiting FcR-driven CD4(+) T cell responses.