Immunomodulatory Functions of BTLA and HVEM Govern Induction of Extrathymic Regulatory T Cells and Tolerance by Dendritic Cells

Abstract

Dendritic cells (DCs) initiate immunity and also antigen-specific tolerance mediated by extrathymic regulatory T (Treg) cells. Yet it remains unclear how DCs regulate induction of such tolerance. Here we report that efficient induction of Treg cells was instructed by BTLA+DEC205+CD8+CD11c+ DCs and the immunomodulatory functions of BTLA. In contrast, T cell activation in steady state by total CD11c+ DCs that include a majority of DCs that do not express BTLA did not induce Treg cells and had no lasting impact on subsequent immune responses. Engagement of HVEM, a receptor of BTLA, promoted Foxp3 expression in T cells through upregulation of CD5. In contrast, T cells activated in the absence of BTLA and HVEM-mediated functions remained CD5lo and therefore failed to resist the inhibition of Foxp3 expression in response to effector cell-differentiating cytokines. Thus DCs require BTLA and CD5-dependent mechanisms to actively adjust tolerizing T cell responses under steady state conditions.

Dendritic Cells As Inducers of Peripheral Tolerance

“…Multiple recombinant chimeric antibodies with variable regions specific for various cell surface receptor molecules expressed on DCs have been produced based on the original design (Box 1). Examples of such chimeric recombinant antibodies that target antigens to either all CD11c + cDCs or specific DCs within the DC1 or DC2 lineages include anti-CD11c-Ag, which targets antigens to all CD11c + DCs [55]; anti-DEC205-Ag, which targets antigens to DCs within the DC1 lineage [30]; anti-Langerin-Ag, which targets antigens to migratory DCs [52]; and anti-DCIR2-Ag, which targets antigens to some DCs within the DC2 lineage [49]. Additionally, anti-Siglec-H-Ag [60] targets tolerogenic antigens to Siglec-H + pDCs.…”

“…Combining the methods of antigen delivery to DCs with diverse genetic mouse models lacking specific subtypes of DCs facilitated the understanding of specific tolerogenic functions of DCs [27, 52, 55] and (Figure 1). The two main lineages of CD11c + cDCs (termed “DC1” and “DC2”) are characterized by the expression of specific surface markers and require different transcription factors for their development and proper localization and functions in lymphoid tissues [34, 79, 80].…”

“…Many transcription factors govern DC1 and DC2 development, including Batf3 and IRF8 which are required for the development of the DC1 subset and IRF4, which is required for normal numbers of DC2 [34, 79, 80]. The results of experiments using Batf3 −/− mice confirmed that DC1 contained DCs that can induce pTreg cells and organ-specific tolerance [55, 81]. However, Batf3 −/− mice show no spontaneous autoimmune inflammation, possibly in part due to the heterogeneity of DCs within the DC1 lineage and an incomplete absence of such DCs in certain genetic backgrounds of experimental mice [82, 83].…”

“…Although an antigenic presentation by all CD11c + DCs initially induced anergy in the responding T cells, such tolerance could not be maintained because the anergic T cells failed to convert into pTreg cells [55]. Strikingly, in the Irf4 −/− mice characterized by the decreased numbers of DC2 in lymphoid organs and a correspondingly increased proportion of the lymphoid resident DC1 population, the same antigens delivered to all CD11c + DCs resulted in a robust induction of pTreg cells [55]. Therefore, efficient induction of pTreg cells and long-lasting immune tolerance relies on compartmentalization of the presentation of antigens by specialized DCs.…”

“…Recent studies suggest that mechanisms of T cell anergy and pTreg cell conversion may be intimately linked and that induction of an anergic state can precede a subsequent conversion of initially-tolerized T cells into pTreg cells [55, 88]. However, not all anergic T cells can become pTreg cells, and the specific mechanisms governing the fates of T cells responding to tolerogenic DCs remain unclear.…”