Abstract
The presence of autoantibodies against 14-3-3ζ in human autoimmune diseases indicates its antigenic function. However, neither the cause nor the consequence of this newly-identified antigenic function of 14-3-3ζ protein is known. To address this, we investigated the immunological functions of 14-3-3ζ by studying ex vivo effects on human peripheral blood mononuclear cells (PBMC) proliferation, polarization, and cytokine production. Exogenous 14-3-3ζ promoted PBMC proliferation and T cell polarization toward Th1 and Th17 populations. Significant increases in IFN-γ and IL-17 levels were observed in the presence of 14-3-3ζ. A specific increase in Th1 cells and IFN-γ production provided strong evidence for MHC class II presentation of 14-3-3ζ antigen. Particularly HLA-DRB1*0401 allele strongly promoted 14-3-3ζ-induced IFN-γ producing cells. In contrast, prednisolone treatment suppressed both 14-3-3ζ-induced T cell polarization and cytokine production. Overall, we show that MHC presentation and the adaptor functions of 14-3-3ζ participate in promoting IFN-γ and IL-17 production, two of the cytokines commonly associated with autoimmune diseases. To the best of our knowledge, this is the first report describing the ex vivo antigenic function of 14-3-3ζ with human PBMC, thereby providing the basis of its immunological role in human diseases.
Highlights
Autoantigens are principal components of autoimmune diseases [1,2,3]
Our results show that 14-3-3ζinduced T cell polarization favors Th1 and Th17 cells in human peripheral blood mononuclear cells (PBMC) ex vivo and has a significant role in promoting IFN-γ and IL17A (IL-17) production
Our study provides a novel insight into the immunological role of 14-3-3ζ that promotes T cell polarization and cytokine production
Summary
Autoantigens are principal components of autoimmune diseases [1,2,3]. Reactivity to a specific antigen is a key determinant of autoimmune and allergic responses, and often correlates with the clinical symptoms [4,5,6]. The complexity of factors including HLA specificity, the presence of antigen-specific T and B cells, and the presence of multiple or overlapping epitopes, are a few of the challenges in the understanding of antigenicity [10] These factors contribute to the limited development of autoimmune disease therapy [9, 11]. In addition to antigenic function, the increased extracellular presence of 14-3-3ζ and other isoforms is known in the context of tissue homeostasis and diseases [19, 21,22,23,24,25] Unlike cellular functions, such as signaling, cellular proliferation, migration, and stress-response [26,27,28], immune functions of 14-3-3 family members are recent and evolving. Our results highlight a novel mechanism to the physiological role of 14-3-3ζ as an immunogen in promoting the inflammatory immune response
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