Tolerance induction to self antigens by peripheral dendritic cells

Abstract

It has been suggested, but not formally demonstrated, that peripheral dendritic cells (DC) alone are capable of tolerance induction by clonal deletion and/or anergy. To resolve such an issue, it is important to develop in vivo systems where DC are the only cells capable of presenting antigen and where a T cell population with a known antigen specificity can be followed. Here we use a transgenic murine model, which expresses the influenza virus hemagglutinin (HA) on B cells and on CD8α+ and CD8α– DC but not on macrophages. If these mice are on a RAG–/– background, one has a model in which only DC present the HA antigen. In these mice, HA‐specific T cells are deleted very efficiently in the thymus and those remaining in the periphery cannot respond to further antigenic stimulation in vitro and cannot eliminate antigen in vivo. By performing adoptive transfers, we show for the first time that self‐antigen presentation exclusively by peripheral DC results in very efficient clonal deletion of the majority of antigen‐specific T cells with the remaining ones in an anergic state. This model will permit us to further address the mechanisms by which DC tolerize or prime T cells and to investigate whether anergy induction by DC is similar to anergy induction by B cells.

Self-antigen presentation by mouse B cells results in regulatory T-cell induction rather than anergy or clonal deletion

“…This time, all recipients were Balb/c-and thus did not express HA on thymic epithelium, but we reconstituted them with TCR-HA Foxp3EGFP bone marrow together with either DCs (bone marrow from Rag Ϫ/Ϫ IgHA mice, D chimera) or B cells (CD19 ϩ cells from IgHA bone marrow, B chimera) expressing HA. Figure 5B-C shows that HA expression by DCs induced very efficient thymic deletion of CD4 ϩ 6.5 ϩ cells, as previously reported, 29 whereas HA expression by B cells did not induce significant thymic deletion. These data are in agreement with the fact that B cells represent a very small population in the thymus and do not delete CD4 ϩ T cells efficiently.…”

“…29 As a result, sorted CD19 ϩ or CD11c ϩ cells from the spleen of Ig-HA mice induced proliferation of HA-specific T cells in vitro ( Figure 3A). In contrast, neither DCs nor B cells from pgk-HA mice were capable of inducing HA-specific proliferation in vitro, unless peptide was added to the culture ( Figure 3A).…”

CD8 blockade promotes the expansion of antigen-specific CD4+ FOXP3+ regulatory T cells in vivo

“…A role for CD8α + DC in limiting T cell responsiveness is also well documented. Examples include failure to support proliferation of T cells [89], inhibition of alloreactive T cell expansion resulting in prolonged cardiac allograft survival [90], and, although not relevant here, the induction of T cell apoptosis [91] including apoptosis of self-reactive T cells [92]. However, CD8α + DC also play a role in inducing primary Th1-type rather than Th2-type responses [93,94].…”

CD8 Blockade Promotes Antigen Responsiveness to Nontolerizing Antigen in Tolerant Mice by Inhibiting Apoptosis of CD4+ T Cells

“…A role for CD8␣ ϩ DC in limiting T cell responsiveness is also well-documented. Examples include failure to support proliferation of T cells (59), inhibition of alloreactive T cell expansion resulting in prolonged cardiac allograft survival (60), and, more relevant to this study, the induction of T cell apoptosis (61) including apoptosis of self-reactive T cells (62). However, CD8␣…”