IgA-Producing B Cells Exert Regulatory Function through Granzyme B in Kidney Allograft Tolerance

Area of Science:

• Immunology
• Transplantation Biology
• Cellular Immunology

Background:

• Tolerant kidney transplant recipients exhibit increased granzyme B (GZMB)-expressing regulatory B cells (Bregs).
• The origin of these Bregs is unknown, and IgA-secreting B cells possess regulatory functions.
• This study investigates the link between IgA and GZMB expression in B cells.

Purpose of the Study:

• To determine the association between IgA-secreting B cells and GZMB-expressing regulatory B cells (Bregs).
• To characterize the phenotype and function of IgA+ B cells in kidney transplant recipients.
• To explore the role of IgA+ Bregs in transplant tolerance.

Main Methods:

• Case-control study including healthy volunteers and kidney transplant recipients (stable, rejection, tolerant).
• Serum immunoglobulin levels, IgA subclasses, and glycosylation analyzed.
• Single-cell RNA sequencing and multiparameter spectral flow cytometry used for B cell analysis.
• Functional assays assessed B cell regulatory capacity in co-culture with T cells.

Main Results:

• Tolerant recipients had elevated serum IgA, particularly the IgA1 subclass.
• Single-cell analysis revealed co-expression of IgA and GZMB genes in B cells.
• IgA+ B cells were identified as memory B cells, with higher GZMB expression in tolerant patients.
• IgA+ B cells demonstrated significant regulatory functions, partially inhibited by GZMB inhibitors.

Conclusions:

• A strong association exists between IgA+ and GZMB+ regulatory B cells (Bregs).
• Tolerant kidney transplant recipients show increased IgA and GZMB expression on Bregs.
• These IgA+ GZMB+ Bregs possess enhanced suppressive properties, contributing to transplant tolerance.