IL-21 Is an Antitolerogenic Cytokine of the Late-Phase Alloimmune Response

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IL-21 Is an Antitolerogenic Cytokine of the Late-Phase Alloimmune Response

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Title: IL-21 Is an Antitolerogenic Cytokine of the Late-Phase Alloimmune Response
Author: Petrelli, Alessandra; Carvello, Michele; Du, Ming; Chengwen, Liu; Mfarrej, Bechara G.; Hwu, Patrick; Secchi, Antonio; Leonard, Warren J.; Young, Deborah; Zajac, Allan J.; Vergani, Andrea; Lee, Kang Mi; Tezza, Sara; Kleffel, Sonja Beate; Sayegh, Mohamed Hassan; Markmann, James F.; Fiorina, Paolo

Note: Order does not necessarily reflect citation order of authors.

Citation: Petrelli, Alessandra, Michele Carvello, Andrea Vergani, Kang Mi Lee, Sara Tezza, Ming Du, Sonja Beate Kleffel, et al. 2011. IL-21 is an antitolerogenic cytokine of the late-phase alloimmune response. Diabetes 60(12): 3223-3234.
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Abstract: Objective: Interleukin-21 (IL-21) is a proinflammatory cytokine that has been shown to affect Treg/Teff balance. However, the mechanism by which IL-21 orchestrates alloimmune response and interplays with Tregs is still unclear. Research design and methods: The interplay between IL-21/IL-21R signaling, FoxP3 expression, and Treg survival and function was evaluated in vitro in immunologically relevant assays and in vivo in allogenic and autoimmune models of islet transplantation. Results: IL-21R expression decreases on T cells and B cells in vitro and increases in the graft in vivo, while IL-21 levels increase in vitro and in vivo during anti-CD3/anti-CD28 stimulation/allostimulation in the late phase of the alloimmune response. In vitro, IL-21/IL-21R signaling (by using rmIL-21 or genetically modified \(CD4^+\) T cells [IL-21 pOrf plasmid–treated or hIL-21-Tg mice]) enhances the T-cell response during anti-CD3/anti-CD28 stimulation/allostimulation, prevents Treg generation, inhibits Treg function, induces Treg apoptosis, and reduces FoxP3 and FoxP3-dependent gene transcripts without affecting FoxP3 methylation status. In vivo targeting of IL-21/IL-21R expands intragraft and peripheral Tregs, promotes Treg neogenesis, and regulates the antidonor immune response, whereas IL-21/IL-21R signaling in Doxa-inducible ROSA-rtTA-IL-21-Tg mice expands Teffs and \(FoxP3^−\) cells. Treatment with a combination of mIL-21R.Fc and CTLA4-Ig (an inhibitor of the early alloimmune response) leads to robust graft tolerance in a purely alloimmune setting and prolonged islet graft survival in NOD mice. Conclusions: IL-21 interferes with different checkpoints of the FoxP3 Treg chain in the late phase of alloimmune response and, thus, acts as an antitolerogenic cytokine. Blockade of the IL-21/IL-21R pathway could be a precondition for tolerogenic protocols in transplantation.
Published Version: doi:10.2337/db11-0880
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3219943/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:10613626
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