IL-10 from marginal zone precursor B cells controls the differentiation of Th17, Tfh and Tfr cells in transplantation tolerance

Abstract

B cells are known to control CD4 T cell differentiation in secondary lymphoid tissues. We hypothesized that IL-10 expression by marginal zone precursor (MZP) regulatory B cells controls the differentiation and positioning of effector and regulatory T cells during tolerization. Costimulatory blockade with donor-specific transfusion (DST) and anti-CD40L mAb in C57BL/6 mice induced tolerance to allogeneic cardiac allograft. B cell depletion or IL-10 deficiency in B cells prevented tolerance, resulting in decreased follicular regulatory CD4+ T cells (Tfr) and increased IL-21 expression by T follicular helper (Tfh) cells in the B cell and T cell zones. IL-21 acted with IL-6 to induce CCR6+ Th17 that caused rejection. Deficiency or blockade of IL-6, IL-21, IL-21R, or CCR6 prevented B cell depletion-induced acute cellular rejection; while agonistic mCCL20-Ig induced rejection. Adoptive transfer of IL-10+/+ MZP in tolerogen treated CD19-Cre+/−::IL-10fl/fl mice rescued the localization of Tfh and Tfr cells in the B cell follicle and prevented allograft rejection. MZP B cell IL-10 is necessary for tolerance and controls the differentiation and position of Th17, Tfh and Tfr cells in secondary lymphoid tissues. This has implications for understanding tolerance induction and how B cell depletion may prevent tolerance.

Transplantation tolerance: don't forget about the B cells

“…IL-10 was increased only in the MZP B cells that up-regulated IL-21R in tolerant recipients, and that were able to promote graft acceptance in B cell-specific IL-10-deficient recipients. These IL-10-producing MZP B cells controlled the differentiation and position of Th17, Tfh and Tfr cells in secondary lymphoid tissues [46], thus providing contrasting mechanistic insights to previous studies on B regs , and underscoring the diversity in phenotype of IL-10-producing B cells that promote transplantation tolerance. Similarly, Durand et al [47] reported that splenic B cells from rats tolerant to allogeneic hearts were enriched for a CD24 int CD38 1 CD27 1 IgD -IgM 1/low regulatory subpopulation that expressed granzyme B and interferon regulatory factor 4 (Irf4) as well as inhibitory CD23 and BANK1.…”

“…IL‐10 was increased only in the MZP B cells that up‐regulated IL‐21R in tolerant recipients, and that were able to promote graft acceptance in B cell‐specific IL‐10‐deficient recipients. These IL‐10‐producing MZP B cells controlled the differentiation and position of Th17, Tfh and Tfr cells in secondary lymphoid tissues , thus providing contrasting mechanistic insights to previous studies on B regs , and underscoring the diversity in phenotype of IL‐10‐producing B cells that promote transplantation tolerance. Similarly, Durand et al .…”

Transduction of interleukin-10 through renal artery attenuates vascular neointimal proliferation and infiltration of immune cells in rat renal allograft

“…Neointimal proliferation and immune infiltration are characteristics of chronic vascular rejection, a process that leads to significant loss of transplanted organ function and may account for decreased long-term graft survival [1][2][3][4]13]. IL-10 is an extensive immune regulator that downregulates the expression of Th1 cytokines, MHC class II antigens, and co-stimulatory molecules on macrophages [29][30][31].…”

“…We previously found that a single intramuscular administration of type 1 adeno-associated viral vector carrying interleukin-10 gene (AAV1-IL-10) increased systemic IL-10, inhibited neointimal proliferation of aortic allograft and prolonged allograft survival in rat models of aortic and kidney transplantation [12]. IL-10 from marginal zone precursor B cells controls the differentiation of Th17,follicular regulatory CD4+ T cells and follicular helper CD4+ T cells in transplantation tolerance [13]. However, many data suggest IL-10 also mediates immunostimulatory properties [10,11,14].…”

Tolerance in Kidney Transplantation: What Is on the B Side?

“…In mice models, multiple studies show that Breg can induce Treg and are capable of transferring tolerance in allogeneic cardiac allograft [75], islet allograft [76], and arthritis [77] models. These studies point out the central role of IL-10 in the modulation of the immune response.…”