title: IL-34 is a Treg-specific cytokine and mediates transplant tolerance.
abstract: Cytokines and metabolic pathway-controlling enzymes regulate immune responses and have potential as powerful tools to mediate immune tolerance. Blockade of the interaction between CD40 and CD40L induces long-term cardiac allograft survival in rats through a CD8+CD45RClo Treg potentiation. Here, we have shown that the cytokine IL-34, the immunoregulatory properties of which have not been previously studied in transplantation or T cell biology, is expressed by rodent CD8+CD45RClo Tregs and human FOXP3+CD45RCloCD8+ and CD4+ Tregs. IL-34 was involved in the suppressive function of both CD8+ and CD4+ Tregs and markedly inhibited alloreactive immune responses. Additionally, in a rat cardiac allograft model, IL-34 potently induced transplant tolerance that was associated with a total inhibition of alloantibody production. Treatment of rats with IL-34 promoted allograft tolerance that was mediated by induction of CD8+ and CD4+ Tregs. Moreover, these Tregs were capable of serial tolerance induction through modulation of macrophages that migrate early to the graft. Finally, we demonstrated that human macrophages cultured in the presence of IL-34 greatly expanded CD8+ and CD4+ FOXP3+ Tregs, with a superior suppressive potential of antidonor immune responses compared with non-IL-34-expanded Tregs. In conclusion, we reveal that IL-34 serves as a suppressive Treg-specific cytokine and as a tolerogenic cytokine that efficiently inhibits alloreactive immune responses and mediates transplant tolerance.
authors.forename: Séverine
authors.initials: S
authors.lastname: Bézie
authors.forename: Elodie
authors.initials: E
authors.lastname: Picarda
authors.forename: Jason
authors.initials: J
authors.lastname: Ossart
authors.forename: Laurent
authors.initials: L
authors.lastname: Tesson
authors.forename: Claire
authors.initials: C
authors.lastname: Usal
authors.forename: Karine
authors.initials: K
authors.lastname: Renaudin
authors.forename: Ignacio
authors.initials: I
authors.lastname: Anegon
authors.forename: Carole
authors.initials: C
authors.lastname: Guillonneau
mesh_terms: D019264:Adoptive Transfer; D064591:Allografts / Q000276:immunology; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D000229:Dependovirus / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000032:analysis; D005822:Genetic Vectors; D057809:HEK293 Cells; D016027:Heart Transplantation; D006801:Humans; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D017493:Leukocyte Common Antigens / Q000032:analysis; D008213:Lymphocyte Activation; D016173:Macrophage Colony-Stimulating Factor / Q000502:physiology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011917:Rats, Inbred Lew; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D046888:Tissue Array Analysis; D014161:Transduction, Genetic; D023001:Transplantation Tolerance
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C500522:Foxp3 protein, rat; C529076:IL34 protein, human; D007378:Interleukins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; C000604173:interleukin-34, rat; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor; D017493:Leukocyte Common Antigens