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 CD4posCXCR5pos Tfh cells and CD19posCD27pos memory 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.

Highlights

  • After kidney transplantation, the immunological barrier between organ donor and recipient still limits graft survival [1]

  • We set up an in vitro system to study the functional interaction of CD4posCXCR5pos T follicular helper (Tfh) cells and CD19posCD27pos memory B cells upon alloantigen stimulation and the role of IL-21 in this response

  • We studied the activation of Tfh and memory B cells upon stimulation with alloantigen and the role of IL-21 within this process

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Summary

Introduction

The immunological barrier between organ donor and recipient still limits graft survival [1] In this setting, a large proportion of allograft recipients develop a donor-specific antibody response associated with an increased risk for chronic rejection [2,3,4,5]. T cell-mediated help to B cells is required for the generation of antigen-specific antibody responses This process is mainly driven via IL-21-secreting T follicular helper (Tfh) cells. Through autocrine and paracrine mechanisms, IL-21 amplifies and stabilizes Tfh cell-mediated responses, B cell proliferation, immunoglobulin class switch recombination (CSR), and B cell differentiation toward plasmablasts and long-living memory B cells [9, 10] In this respect, IL-21 directly effects B cell responses via IL-21 receptor (IL-21R) expressed on the B cells [11, 12]. The circulating counterparts of the “GC-Tfh cells” in humans express CXCR5, low expression levels of PD-1 and ICOS and lack expression of transcription repressor Bcl-6 [16,17,18]

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