Peripheral CD4⁺T‐cell tolerance is induced in vivo by rare antigen‐bearing B cells in follicular, marginal zone, and B‐1 subsets

Abstract

Summary B cells are efficient APCs when they internalize antigen via BCR-mediated uptake. Adoptively transferred antigen-presenting B cells can induce T-cell tolerance to foreign and self antigens; however, it is unknown whether endogenous B cells presenting self-peptides interact with naïve T cells and contribute to peripheral T-cell self-tolerance. Moreover, the relative abilities of mature B-cell subsets to induce T-cell tolerance have not been examined. To address these questions, we created a new mouse model wherein a very small fraction of B cells expresses an antigen transgene that cannot be transferred to other APCs. We limited antigen expression to follicular, marginal zone, or B-1 B-cell subsets and found that small numbers of each subset interacted with naïve antigen-specific T cells. Although antigen expressed by B-1 B cells induced the most T-cell division, divided T cells subsequently disappeared from secondary lymphoid tissues. Independent of which B-cell subset presented antigen, the remaining T cells were rendered hyporesponsive, and this effect was not associated with Foxp3 expression. Our data show that physiologically relevant proportions of B cells can mediate peripheral T-cell tolerance, and suggest that the mechanisms of tolerance induction might differ among follicular, marginal zone, and B-1 B-cell subsets.

Characterization of c-Maf+Foxp3− Regulatory T Cells Induced by Repeated Stimulation of Antigen-Presenting B Cells

“…This observation was consistent with that self-antigen-bearing B cells stimulated antigen-specific T cells proliferation in vivo 1338. B-cells-activated self-antigen-specific CD4 + T cells decreased proliferative capacity ex vivo 123940, and which unresponsiveness without association with Foxp3 expression13. Addition to self-antigens, genetically B cell-deficient mice had a defected tolerogenic response to antigen from the oral route or nasal route841.…”

Regulatory T cells in B‐cell‐deficient and wild‐type mice differ functionally and in expression of cell surface markers

“…B cells have both positive and negative effects on immune responses and autoimmune diseases . B cells can induce tolerance in CD4 + T cells, primarily by producing IL‐10 or other suppressive cytokines . B cells also function as regulatory cells, whereby a specialized subset of IL‐10‐producing B cells can inhibit immune responses and autoimmune diseases .…”

“…[47][48][49][58][59][60] B cells can induce tolerance in CD4 + T cells, primarily by producing IL-10 or other suppressive cytokines. 47,49,58,[61][62][63] B cells also function as regulatory cells, whereby a specialized subset of IL-10-producing B cells can inhibit immune responses and autoimmune diseases. 47,48,58,60,[63][64][65] However, in autoimmune diseases such as SAT that require B cells for their development, B cells function primarily as APC to initiate disease.…”

Regulatory T cells induced by B cells: a novel subpopulation of regulatory T cells

“…Raimondi et al demonstrated that adoptive transfer of antigen-presenting B cells four times in a week lead to antigen-specific CD4 + T cells tolerance independent of naïve or activated B cells [ 60 , 61 ]. Antigen-presenting follicular B, marginal zone B, and B-1a cells rendered antigen-specific T cells hyporesponsiveness without Foxp3 + Treg cells induction [ 62 ]. One study reported that B cells contributed to Treg cells homeostasis and cooperated with Treg cells to ameliorate inflammation [ 63 ].…”