The phenotype of HLA-binding B cells from sensitized kidney transplant recipients correlates with clinically prognostic patterns of interferon-γ production against purified HLA proteins

TY - JOUR

T1 - The phenotype of HLA-binding B cells from sensitized kidney transplant recipients correlates with clinically prognostic patterns of interferon-γ production against purified HLA proteins

AU - Burton, Hannah

AU - McLaughlin, Laura

AU - Shiu, Kin Yee

AU - Shaw, Olivia

AU - Mamode, Nizam

AU - Spencer, Jo

AU - Dorling, Anthony

N1 - Funding Information: The authors would like to thank the patients, nursing staff, and physicians at Guy’s Hospital. The authors acknowledge that the research was funded/supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. This study was funded by an MRC/KRUK Clinical Research Training Fellowship for HB (MR/M01813X/1 // JF1/2015), a project grant from Kidney Research UK (RP3/2011), and generous donations from the GSTT Kidney Patients Association. Funding Information: The authors would like to thank the patients, nursing staff, and physicians at Guy's Hospital. The authors acknowledge that the research was funded/supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. This study was funded by an MRC/KRUK Clinical Research Training Fellowship for HB (MR/M01813X/1 // JF1/2015), a project grant from Kidney Research UK (RP3/2011), and generous donations from the GSTT Kidney Patients Association. Publisher Copyright: © 2022 International Society of Nephrology

PY - 2022/8

Y1 - 2022/8

N2 - 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 and 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 hypothesized that studying antigen-specific B cells, using samples from sensitized patients, 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 associated with patterns of anti-HLA response in interferon-γ ELISpot. HLA-binding class-switched and IgM+CD27+ memory cells associated strongly with B-dependent interferon-γ 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. High numbers of non-HLA-binding transitional cells associated with B-suppressed interferon-γ production, especially if Tregs were present. However, high frequencies of HLA-binding marginal-zone precursors associated with B-dependent interferon-γ production that appeared suppressible by Tregs. Finally, non-HLA-binding marginal zone precursors may also suppress interferon-γ production, though this association only emerged when Tregs were absent from the ELISpot. Thus, our novel data provide a foundation on which to further define the complexities of interactions between HLA-specific T and B cells and identify new targets for intervention in new therapies for chronic rejection.

AB - 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 and 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 hypothesized that studying antigen-specific B cells, using samples from sensitized patients, 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 associated with patterns of anti-HLA response in interferon-γ ELISpot. HLA-binding class-switched and IgM+CD27+ memory cells associated strongly with B-dependent interferon-γ 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. High numbers of non-HLA-binding transitional cells associated with B-suppressed interferon-γ production, especially if Tregs were present. However, high frequencies of HLA-binding marginal-zone precursors associated with B-dependent interferon-γ production that appeared suppressible by Tregs. Finally, non-HLA-binding marginal zone precursors may also suppress interferon-γ production, though this association only emerged when Tregs were absent from the ELISpot. Thus, our novel data provide a foundation on which to further define the complexities of interactions between HLA-specific T and B cells and identify new targets for intervention in new therapies for chronic rejection.

KW - chronic allograft nephropathy

KW - inflammation

KW - lymphocytes

KW - transplantation

UR - http://www.scopus.com/inward/record.url?scp=85130400254&partnerID=8YFLogxK

U2 - 10.1016/j.kint.2022.02.041

DO - 10.1016/j.kint.2022.02.041

M3 - Article

C2 - 35483526

AN - SCOPUS:85130400254

SN - 0085-2538

VL - 102

SP - 355

EP - 369

JO - Kidney International

JF - Kidney International

IS - 2

ER -