title: IL-21 Receptor Antagonist Inhibits Differentiation of B Cells toward Plasmablasts upon Alloantigen Stimulation.
abstract: Interaction between T follicular helper (Tfh) cells and B cells is complex and involves various pathways, including the production of IL-21 by the Tfh cells. Secretion of IL-21 results in B cell differentiation toward immunoglobulin-producing plasmablasts. In patients after kidney transplantation, the formation of alloantibodies produced by donor antigen-activated B cells are a major cause of organ failure. In this allogeneic response, the role of IL-21-producing Tfh cells that regulate B cell differentiation is unknown. Here, we tested, in an alloantigen-driven setting, whether Tfh cell help signals control B cell differentiation with its dependency on IL-21. Pre-transplantation patient PBMCs were sorted into pure CD4posCXCR5posTfh cells and CD19posCD27posmemory B cells and stimulated with donor antigen in the presence or absence of an IL-21 receptor (IL-21R) antagonist (αIL-21R). Donor antigen stimulation initiated expression of the activation markers inducible co-stimulator (ICOS) and programmed death 1 (PD-1) on Tfh cells and a shift toward a mixed Tfh2 and Tfh17 phenotype. The memory B cells underwent class switch recombination and differentiated toward IgM- and IgG-producing plasmablasts. In the presence of αIL-21R, a dose-dependent inhibition of STAT3 phosphorylation was measured in both T and B cells. Blockade of the IL-21R did not have an effect on PD-1 and ICOS expression on Tfh cells but significantly inhibited B cell differentiation. The proportion of plasmablasts decreased by 78% in the presence of αIL-21R. Moreover, secreted IgM and IgG2 levels were significantly lower in the presence of αIL-21R. In conclusion, our results demonstrate that IL-21 produced by alloantigen-activated Tfh cells controls B cell differentiation toward antibody producing plasmablasts. The IL-21R might, therefore, be a useful target in organ transplantation to prevent antigen-driven immune responses leading to graft failure.
authors.affiliation: Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, Netherlands; Division of HPB and Transplant Surgery, Department of Surgery, Erasmus MC, University Medical Center, Rotterdam, Netherlands.
authors.forename: Kitty
authors.initials: K
authors.lastname: de Leur
authors.affiliation: Division of HPB and Transplant Surgery, Department of Surgery, Erasmus MC, University Medical Center , Rotterdam , Netherlands.
authors.forename: Frank J M F
authors.initials: FJ
authors.lastname: Dor
authors.affiliation: Department of Internal Medicine, Erasmus MC, University Medical Center , Rotterdam , Netherlands.
authors.forename: Marjolein
authors.initials: M
authors.lastname: Dieterich
authors.affiliation: Division of HPB and Transplant Surgery, Department of Surgery, Erasmus MC, University Medical Center , Rotterdam , Netherlands.
authors.forename: Luc J W
authors.initials: LJ
authors.lastname: van der Laan
authors.affiliation: Department of Pulmonary Medicine, Erasmus MC, University Medical Center , Rotterdam , Netherlands.
authors.forename: Rudi W
authors.initials: RW
authors.lastname: Hendriks
authors.affiliation: Department of Internal Medicine, Erasmus MC, University Medical Center , Rotterdam , Netherlands.
authors.forename: Carla C
authors.initials: CC
authors.lastname: Baan
keywords: B cell differentiation; IL-21 receptor; alloreactivity; follicular T-helper cell; plasmablast