Infusion of Dendritic Cells Carrying Donor Lymphocytes Treated With 8-Methoxypsoralen and Ultraviolet A Light Induces CD19+IL-10+ Regulatory B cells and Promotes Skin Allograft Survival

Abstract Regulatory dendritic cells (DCs) play important roles in the induction of peripheral tolerance and control of adaptive immune response. Our previous studies demonstrate that splenic stroma can drive mature DCs to proliferate and further differentiate into a unique subset of CD11bhiIalow regulatory DCs, which could inhibit T-cell response, program generation of immunosuppressive memory CD4 T cells. However, the effect of regulatory DCs on B-cell function remains unclear. Here, we report that regulatory DCs can induce splenic B cells to differentiate into a distinct subtype of IL-10–producing regulatory B cells with unique phenotype CD19hiFcγIIbhi. CD19hiFcγIIbhi B cells inhibit CD4 T-cell response via IL-10. CD19hiFcγIIbhi B cells have enhanced phagocytic capacity compared with conventional CD19+ B cells, and FcγRIIb mediates the uptake of immune complex by CD19hiFcγIIbhi B cells. We found that regulatory DC-derived IFN-β and CD40 ligand are responsible for the differentiation of CD19hiFcγIIbhi B cells. Furthermore, an in vivo counterpart of CD19hiFcγIIbhi B cells in the spleen and lymph nodes with similar phenotype and regulatory function has been identified. Our results demonstrate a new manner for regulatory DCs to down-regulate immune response by, at least partially, programming B cells into regulatory B cells.

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Cyclic Helix B Peptide Prolongs Skin Allograft Survival via Inhibition of B Cell Immune Responses in a Murine Model

Frontiers in Immunology ◽

10.3389/fimmu.2021.682749 ◽

2021 ◽

Vol 12 ◽

Author(s):

Long Zheng ◽

Xuanchuan Wang ◽

Linkun Hu ◽

Wenjun Gao ◽

Weitao Zhang ◽

...

Keyword(s):

B Cells ◽

Immune Responses ◽

B Cell ◽

Plasma Cells ◽

Cell Infiltration ◽

Skin Transplantation ◽

Allograft Survival ◽

Skin Allograft ◽

Tfh Cells ◽

Transplantation Model

Antibody-mediated rejection (AMR) represents a major cause of allograft dysfunction and results in allograft failure in solid organ transplantation. Cyclic helix B peptide (CHBP) is a novel erythropoietin-derived peptide that ameliorated renal allograft rejection in a renal transplantation model. However, its effect on AMR remains unknown. This study aimed to investigate the effect of CHBP on AMR using a secondary allogeneic skin transplantation model, which was created by transplanting skin from BALB/c mice to C57BL/6 mice with or without CHBP treatment. A secondary syngeneic skin transplantation model, involving transplantation from C57BL/6 mice to C57BL/6 mice, was also created to act as a control. Skin graft rejection, CD19+ B cell infiltration in the skin allograft, the percentages of splenic plasma cells, germinal center (GC) B cells, and Tfh cells, the serum levels of donor specific antibodies (DSAs), and NF-κB signaling in splenocytes were analyzed. Skin allograft survival was significantly prolonged in the CHBP group compared to the allogeneic group. CHBP treatment also significantly reduced the CD19+ B cell infiltration in the skin allograft, decreased the percentages of splenic plasma cells, GC B cells, and Tfh cells, and ameliorated the increase in the serum DSA level. At a molecular level, CHBP downregulated P100, RelB, and P52 in splenocytes. CHBP prolonged skin allograft survival by inhibiting AMR, which may be mediated by inhibition of NF-κB signaling to suppress B cell immune responses, thereby decreasing the DSA level.

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