Tolerance without Clonal Expansion: Self-Antigen-Expressing B Cells Program Self-Reactive T Cells for Future Deletion

Abstract

2), it was presumed that anti-IgD Abs targeted resting B cells, and due to a lack of costimulatory molecules, these B cells tolerized MBP-specific T cells. Similarly, it was shown that passive transfer of B cells expressing a myelin peptide prevented the induction of EAE (6 -8) or even EAE relapses (9). One explanation why B cells induce tolerance of naive but not memory T cells might be the need for expression of costimulatory molecules by the APC to activate naive T cells, specifically B7-1 and/or B7-2, but resting B cells do not express these molecules. On the other hand, memory T cells may not need costimulation and could therefore be activated by B cells. A problem of this hypothesis is that also activated B cells, which normally do express B7 molecules, can induce tolerance of T cells (10). It is therefore not clear whether it is indeed the absence of costimulation what causes B cells to induce tolerance.To study the role of B cells in tolerance induction we have generated mice that express an MHC class II-restricted immunodominant T cell epitope of myelin oligodendrocyte glycoprotein (MOG) specifically on B cells. These mice were found to be resistant to EAE induction. We could show that, following interaction of naive T cells with B cells presenting their specific Ag, T cells are partially activated, resulting in very marginal proliferation and up-regulation of coinhibitory molecules such as CTLA-4, B and T lymphocyte attenuator (BTLA), PD-1, and CD5. Subsequent in vivo activation of tolerized T cells leads to their deletion. Thus, we assessed that naive B cells induce peripheral tolerance by inducing expression of negative costimulatory molecules by Ag-specific T cells, followed by Ag-induced cell death (AICD) upon the next Ag encounter. Materials and Methods Generation of invariant chain (Ii) MOG miceThe targeting vector ROSA26STOP*IiMOG was constructed by introduction into the XbaI site of the vector ROSA26 -1 (11); a gift from P. Soriano (Fred Hutchinson Cancer Research Center, Seattle, WA) of a fragment comprising (5Ј to 3Ј): adenoviral splice acceptor, loxP, 2ϫ SV40 polyadenylation signal, FRT-flanked pGK-neo, a STOP cassette (12), loxP, mutant invariant chain (termed IiMOG), and bovine poly(A). The mutant invariant chain (IiMOG) was generated by assembly PCR on Ii template cDNA (derived from plasmid pcEX V3 mIi31, carrying the cDNA of the

Expression of Natural Autoantibodies in MRL-lpr Mice Protects from Lupus Nephritis and Improves Survival

“…There is clear evidence that B cells as APC can induce T cell tolerance (68)(69)(70)(71). In some reports, it has been shown that tolerance induction was mediated by upregulation of negative costimulatory molecules such as CTLA-4 and programmed cell death-1 on T cells (70,71). Our finding that the ppc1-5H MRLlpr mice have increased numbers of CTLA-4 + T cells suggest that the ppc1-5H NAA B cells may be able to deliver a tolerogenic signal to CD4 + T cells.…”

Antibody-mediated B-cell depletion before adoptive immunotherapy with T cells expressing CD20-specific chimeric T-cell receptors facilitates eradication of leukemia in immunocompetent mice

“…10 Although B cells can exhibit tolerogenic properties when stimulating naive T cells, little is known about in vivo reactivation of effector T cells by antigen-expressing naive B cells. [11][12][13][14] Clinical experience suggests cTCR ϩ T cells are diminished in the blood of patients with large antigen burdens, 4,15 but it is unclear to what extent this rapid clearance represents deletion or retention at antigen rich sites. Global lymphodepletion has been shown to increase T-cell survival, 16,17 but the effect of selective B-cell lymphodepletion before adoptive transfer of B-cell antigenspecific T cells has not been evaluated.…”

B Lymphocytes Treated In Vitro with Antigen Coupled to Cholera Toxin B Subunit Induce Antigen-Specific Foxp3+ Regulatory T Cells and Protect against Experimental Autoimmune Encephalomyelitis

“…Previous efforts to generate B cells with suppressive functions for use in cell therapy have mainly focused on either activating naive B cells with Ab to CD40 (20,21,28) or activating the cells with LPS or other TLR ligands and transducing the cells with retroviral vectors expressing relevant auto-Ags (16,19,29). In this study, we describe another approach through which Breg cells can be efficiently generated by simply incubating naive B cells with a relevant Ag conjugated to CTB for ca.…”