IL-21 Is an Antitolerogenic Cytokine of the Late-Phase Alloimmune Response
نویسندگان
چکیده
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.
منابع مشابه
Changes in some pro-and anti-inflammatory cytokines produced by bovine peripheral blood mononuclear cells following foot and mouth disease vaccination
Interleukin (IL)-17 is exclusively produced by CD4 helper T-cells upon activation. It most often acts as a pro-inflammatory cytokine, which stimulates the release of pro-inflammatory cytokines IL-6, IL-8, TNF-α, and granulocyte-macrophage colony-stimulating factor (GM-CSF). In this study, we studied the in-vitro IL-17 response to specific antigens and a variety of mitogens and compared the IL-1...
متن کاملThe Role of Interleukin (IL-22) in immune response to human diseases
Background and aims: IL-22 is an alpha- helical cytokine. IL-22 binds to a heterodimeric cell surface receptor composed of IL-10R2 and IL-22R1subunits. IL-22R is expressed on tissue cells, and it is absent on immune cells. L-22 and IL-10 receptor chains play a role in cellular targeting and signal transduction to selectively initiate and regulate immune responses. The aim of this study was to i...
متن کاملIL-17 is Aberrantly Overexpressed Among Under-treatment Systemic Lupus Erythematosus Patients
Background & Objective: Systemic lupus erythematosus (SLE) is an autoimmune disease with chronic inflammatory immune response. Current therapies mostly rely on glucocorticoids which are accompanied by side-effects and mostly fail to achieve a favorable remission. Th17 subpopulation of T cells is increased in exacerbated SLE as IL-17 cytokine is overexpressed. ...
متن کاملCYTOKINE AND GROWTH FACTOR MODULATION OF CELL CYCLE EVENTS IN HUMAN MELANOMA CELL LINES
Cytokines influence cell cycle events, which in some but not all instances can be associated with melanoma progression. Analysis of the G0/G 1 and S phase fractions of the cell cycle was used to assay the proliferative or inhibitory activity of cytokines against ten human melanoma cell lines, including pairs of cell lines derived from primary and metastatic tissue of individual patients. Cy...
متن کاملSerum Level of Selenium, IL-4, IL-10 & IFN-g in Patients with Allergic Asthma, Allergic Rhinitis and Healthy Controls
Background: Allergic diseases have increased during the past decade worldwide. Th2 type lymphocyte response is known to play an important role in the process of allergic inflammation. IL-4, a mediator of type II cytokine response increases IgE synthesis and Interferon gamma, a cytokine of type I response interferes with IL-4 and inhibits IgE production. Selenium is an essential component of glu...
متن کامل