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    Partial cD25 antagonism enables Dominance of antigen-inducible cD25high FOXP3+ regulatory T cells as a Basis for a regulatory T cell- Based adoptive immunotherapy

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    Author
    Wilkinson, Daniel S.; Ghosh, Debjani; Nickle, Rebecca A.; Moorman, Cody D.; Mannie, Mark D.
    Abstract
    FOXP3+ regulatory T cells (Tregs) represent a promising platform for effective adoptive immunotherapy of chronic inflammatory disease, including autoimmune diseases such as multiple sclerosis. Successful Treg immunotherapy however requires new technologies to enable long-term expansion of stable, antigen-specific FOXP3+ Tregs in cell culture. Antigen-specific activation of naïve T cells in the presence of TGF-β elicits the initial differentiation of the FOXP3+ lineage, but these Treg lines lack phenotypic stability and rapidly transition to a conventional T cell (Tcon) phenotype during in vitro propagation. Because Tregs and Tcons differentially express CD25, we hypothesized that anti-CD25 monoclonal antibodies (mAbs) would only partially block IL-2 signaling in CD25high FOXP3+ Tregs while completely blocking IL-2 responses of CD25low-intermediate Tcons to enable preferential outgrowth of Tregs during in vitro propagation. Indeed, murine TGF-β- induced MOG-specific Treg lines from 2D2 transgenic mice that were maintained in IL-2 with the anti-CD25 PC61 mAb rapidly acquired and indefinitely maintained a FOXP3high phenotype during long-term in vitro propagation (>90% FOXP3+ Tregs), whereas parallel cultures lacking PC61 rapidly lost FOXP3. These results pertained to TGF-β-inducible “iTregs” because Tregs from 2D2-FIG Rag1−/− mice, which lack thymic or natural Tregs, were stabilized by continuous culture in IL-2 and PC61. MOG-specific and polyclonal Tregs upregulated the Treg-associated markers Neuropilin-1 (NRP1) and Helios (IKZF2). Just as PC61 stabilized FOXP3+ Tregs during expansion in IL-2, TGF-β fully stabilized FOXP3+ Tregs during cellular activation in the presence of dendritic cells and antigen/ mitogen. Adoptive transfer of blastogenic CD25high FOXP3+ Tregs from MOG35-55- specific 2D2 TCR transgenic mice suppressed experimental autoimmune encephalomy- elitis in pretreatment and therapeutic protocols. In conclusion, low IL-2 concentrations coupled with high PC61 concentrations constrained IL-2 signaling to a low-intensity range that enabled dominant stable outgrowth of suppressive CD25high FOXP3+ Tregs. The ability to indefinitely expand stable Treg lines will provide insight into FOXP3+ Treg physiology and will be foundational for Treg-based immunotherapy.
    URI
    http://hdl.handle.net/10342/8256
    Date
    2017-12-14
    Citation:
    APA:
    Wilkinson, Daniel S., & Ghosh, Debjani, & Nickle, Rebecca A., & Moorman, Cody D., & Mannie, Mark D.. (December 2017). Partial cD25 antagonism enables Dominance of antigen-inducible cD25high FOXP3+ regulatory T cells as a Basis for a regulatory T cell- Based adoptive immunotherapy. Frontiers in Immunology, (. Retrieved from http://hdl.handle.net/10342/8256

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    MLA:
    Wilkinson, Daniel S., and Ghosh, Debjani, and Nickle, Rebecca A., and Moorman, Cody D., and Mannie, Mark D.. "Partial cD25 antagonism enables Dominance of antigen-inducible cD25high FOXP3+ regulatory T cells as a Basis for a regulatory T cell- Based adoptive immunotherapy". Frontiers in Immunology. . (.), December 2017. August 11, 2022. http://hdl.handle.net/10342/8256.
    Chicago:
    Wilkinson, Daniel S. and Ghosh, Debjani and Nickle, Rebecca A. and Moorman, Cody D. and Mannie, Mark D., "Partial cD25 antagonism enables Dominance of antigen-inducible cD25high FOXP3+ regulatory T cells as a Basis for a regulatory T cell- Based adoptive immunotherapy," Frontiers in Immunology 8, no. (December 2017), http://hdl.handle.net/10342/8256 (accessed August 11, 2022).
    AMA:
    Wilkinson, Daniel S., Ghosh, Debjani, Nickle, Rebecca A., Moorman, Cody D., Mannie, Mark D.. Partial cD25 antagonism enables Dominance of antigen-inducible cD25high FOXP3+ regulatory T cells as a Basis for a regulatory T cell- Based adoptive immunotherapy. Frontiers in Immunology. December 2017; 8() . http://hdl.handle.net/10342/8256. Accessed August 11, 2022.
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