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Enhanced interaction between SEC2 mutant and TCRVβ induces MHC II-independent activation of T cells via PKCθ/NF-κB and IL-2R/STAT5 signaling pathways.

SEC2, a MHC II-dependent T cell mitogen, binds MHC II and TCR Vβs to induce effective co-stimulating signals for clonal T cell expansion. We previously characterized a SEC2 mutant with increased recognition to TCR Vβs, ST-4, which could intensify NF-κB signaling transduction, leading to IL-2 production and T cell activation. In this study, we found that in contrast to SEC2, ST-4 could induce murine CD4+ T cell proliferation in a Vβ8.2- and Vβ8.3-specific manner in the absence of MHC II+ APCs. Furthermore, although IL-2 secretion in response to either SEC2 or ST-4 stimulation was accompanied by upregulation of PKCθ, IKKα/β, IκBα, and NF-κB in mouse splenocytes, only ST-4 could activate CD4+ T cells in the absence of MHC II+ APCs through the PKCθ/NF-κB signaling pathway. The PKCθ inhibitor AEB071 significantly suppressed SEC2/ST-4-induced T cell proliferation, CD69 and CD25 expression, and IL-2 secretion with or without MHC II+ APCs. Further, SEC2/ST-4-induced changes in PKCθ/NF-κB signaling were significantly relieved by AEB071 in a dose-dependent manner. Using Lck siRNA, we found that Lck controlled SEC2/ST-4-induced phosphorylation of PKCθ. We also demonstrated the IL-2R/STAT5 pathway is essential for SEC2/ST-4 -induced T-cell activation. Collectively, our data demonstrate an enhanced ST-4-TCR interaction can compensate for lack of MHC II and stimulate MHC II free CD4+ T cell proliferation via PKCθ/NF-ĸB and IL-2R/STAT5 signaling pathways. Compared with SEC2, intensified PKCθ/NF-ĸB and IL-2R/STAT5 signals induced by ST-4 leads to enhanced T cell activation. The results of this study will facilitate better understanding of TCR-based immunotherapies for cancer.

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