IL-21 Is an Antitolerogenic Cytokine of the Late-Phase Alloimmune Response
- Alessandra Petrelli1,2,
- Michele Carvello3,4,
- Andrea Vergani1,2,
- Kang Mi Lee3,
- Sara Tezza1,
- Ming Du5,
- Sonja Kleffel1,
- Liu Chengwen6,
- Bechara G. Mfarrej1,
- Patrick Hwu6,
- Antonio Secchi2,
- Warren J. Leonard7,
- Deborah Young8,
- Mohamed H. Sayegh1,
- James F. Markmann3,
- Allan J. Zajac5 and
- Paolo Fiorina1,2⇓
- 1Transplantation Research Center, Children’s Hospital, Harvard Medical School, Boston, Massachusetts
- 2Department of Medicine, San Raffaele Scientific Institute, Milan, Italy
- 3Transplant Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
- 4Gastrointestinal Surgery, San Raffaele Scientific Institute, Milan, Italy
- 5Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama
- 6Department of Melanoma Medical Oncology, Center for Cancer Immunology Research, University of Texas M.D. Anderson Cancer Center, Houston, Texas
- 7Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
- 8Immunology and Inflammation, Pfizer, Cambridge, Massachusetts
- Corresponding author: Paolo Fiorina, .
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db11-0880/-/DC1.
- Received June 25, 2011.
- Accepted September 22, 2011.
- © 2011 by the American Diabetes Association.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.