The phenotype of HLA-binding B-cells from sensitised renal transplant recipients correlates with clinically prognostic patterns of IFNγ production against purified HLA proteins

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Abstract

B-cells play crucial roles in cell-mediated alloimmune responses. In vitro, B-cells can support or regulate indirect T-cell alloreactivity in response to donor antigens on ELISpot; these patterns associate with clinical outcome. Previous reports of associations between B-cell phenotype and function have examined global phenotypes and responses to polyclonal stimuli. We hypothesised that studying antigen-specific B-cells, using samples from sensitised patients enrolled in two clinical studies, would inform further study to identify novel targets for intervention.
Using biotinylated HLA proteins, which bind HLA-specific B-cells via the B-cell receptor in a dose-dependent fashion, we report the specific phenotype of HLA-binding B-cells and define how they associate with patterns of anti-HLA response in IFNg ELISpot. HLA-binding class-switched and IgM+CD27+ memory cells associated strongly with B-dependent IFNg production and appeared not suppressible by endogenous Tregs. When the predominant HLA-binding phenotype was naïve B-cells, the associated functional ELISpot phenotype was determined by other cells present: if high numbers of non-HLA-binding transitional cells, then this associated with B-suppressed IFNg production, especially if Tregs were present. However, if high frequencies of HLA-binding marginal-zone precursors (MZP) were present, these associated with B-dependent IFNg production that appeared suppressible by Tregs. Finally, non-HLA-binding MZP may also be able to suppress IFNg production, though this association only emerged when Tregs were absent from the ELISpot. These novel data provide a foundation on which to further define the complexities of interactions between HLA-specific T- and B-cells, to identify new targets for intervention in new therapies for chronic rejection.
Original languageEnglish
Pages (from-to)355-369
JournalKidney International
Volume102
Issue number2
Early online date25 Apr 2022
Publication statusPublished - 21 Jul 2022

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