IL-21 is an antitolerogenic cytokine of the late-phase alloimmune response

Alessandra Petrelli, Michele Carvello, Andrea Vergani, Kang Mi Lee, Sara Tezza, Ming Du, Sonja Kleffel, Liu Chengwen, Bechara G. Mfarrej, Patrick Hwu, Antonio Secchi, Warren J. Leonard, Deborah Young, Mohamed H. Sayegh, James F. Markmann, Allan J. Zajac, Paolo Fiorina

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)3223-3234
Number of pages12
JournalDiabetes
Volume60
Issue number12
DOIs
Publication statusPublished - Dec 2011

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Petrelli, A., Carvello, M., Vergani, A., Lee, K. M., Tezza, S., Du, M., Kleffel, S., Chengwen, L., Mfarrej, B. G., Hwu, P., Secchi, A., Leonard, W. J., Young, D., Sayegh, M. H., Markmann, J. F., Zajac, A. J., & Fiorina, P. (2011). IL-21 is an antitolerogenic cytokine of the late-phase alloimmune response. Diabetes, 60(12), 3223-3234. https://doi.org/10.2337/db11-0880