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TNFα priming enhances CD4+FoxP3+ regulatory T cell suppressive function in murine GvHD prevention and treatment.

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Pierini A, Strober W, Moffett C, Baker J, Nishikii H, Alvarez M, Pan Y, Schneidawind D, Meyer E, Negrin RS,


Pierini A, Strober W, Moffett C, Baker J, Nishikii H, Alvarez M, Pan Y, Schneidawind D, Meyer E, Negrin RS, (click to view)

Pierini A, Strober W, Moffett C, Baker J, Nishikii H, Alvarez M, Pan Y, Schneidawind D, Meyer E, Negrin RS,

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Blood 2016 6 30() pii

Abstract

CD4(+)CD25(+)FoxP3(+) regulatory T cells (Treg) have been shown to effectively prevent graft versus host disease (GvHD) when adoptively transferred in murine models of hematopoietic cell transplantation and in phase I/II clinical trials. Critical limitations to Treg clinical application are the paucity of cells and limited knowledge of the mechanisms of in vivo function. We hypothesized that inflammatory conditions in GvHD modify Treg characteristics and activity. We found that peripheral blood of recipient animals during acute GvHD induces Treg activation and enhances their function. The serum contains high levels of TNFα that selectively activates Treg without impacting CD4(+)FoxP3(-) T cells. TNFα-priming induces Treg in vivo proliferation, while limits CD4 and CD8 conventional T cells (Tcon) ability to proliferate and induce GvHD. TNFα-primed Treg prolong animal survival as compared to unprimed-Treg when used at an unfavorable Treg:Tcon ratio, demonstrating enhanced in vivo efficacy of TNFα-primed Treg. As TNFα is produced by several immune cells during inflammation, our work elucidates aspects of the physiologic mechanisms of Treg function. Furthermore TNFα-priming of Treg provides a new tool to optimize Treg cellular therapies for GvHD prevention and treatment.

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