Tolerogenic Semimature Dendritic Cells Suppress Experimental Autoimmune Thyroiditis by Activation of Thyroglobulin-Specific CD4+CD25+ T Cells

Abstract

Ex vivo treatment of bone marrow-derived dendritic cells (DCs) with TNF-α has been previously shown to induce partial maturation of DCs that are able to suppress autoimmunity. In this study, we demonstrate that i.v. administration of TNF-α-treated, semimature DCs pulsed with thyrogloblin (Tg), but not with OVA Ag, inhibits the subsequent development of Tg-induced experimental autoimmune thyroiditis (EAT) in CBA/J mice. This protocol activates CD4+CD25+ T cells in vivo, which secrete IL-10 upon specific recognition of Tg in vitro and express regulatory T cell (Treg)-associated markers such as glucocorticoid-induced TNFR, CTLA-4, and Foxp3. These CD4+CD25+ Treg cells suppressed the proliferation and cytokine release of Tg-specific, CD4+CD25− effector cells in vitro, in an IL-10-independent, cell contact-dependent manner. Prior adoptive transfer of the same CD4+CD25+ Treg cells into CBA/J hosts suppressed Tg-induced EAT. These results demonstrate that the tolerogenic potential of Tg-pulsed, semimature DCs in EAT is likely to be mediated through the selective activation of Tg-specific CD4+CD25+ Treg cells and provide new insights for the study of Ag-specific immunoregulation of autoimmune diseases.

Sulfamethoxazole and Its Metabolite Nitroso Sulfamethoxazole Stimulate Dendritic Cell Costimulatory Signaling

“…For instance, RelB-deficient dendritic cells fail to up-regulate CD40 in response to LPS, but up-regulate CD80 and CD86 normally, and are incapable of effective Ag-specific priming (71). So called partial dendritic cell maturation (i.e., increased expression of only certain costimulatory receptors or increased expression of costimulatory receptors but no cytokine secretion) has been associated with the induction of tolerogenic, rather than pathogenic, T cell responses (72,73). In this respect, one must note that binding of the natural CD40L CD154 to dendritic cells expressing high levels of the CD40R stimulates further dendritic cell maturation and, as such, the observed highly specific effect of SMX metabolites on CD40 may, in a mixed cell population, ultimately result in fully matured dendritic cells.…”

Similar inflammatory DC maturation signatures induced by TNF or Trypanosoma brucei antigens instruct default Th2‐cell responses

“…Later, other autoimmune diseases such as thyroiditis and arthritis were also prevented by the application of TNF-matured DCs [31,32]. The protective response as induced by three injections of TNF-conditioned DCs in the EAE setting was controlled by the simultaneous activation of CD1d-dependent NKT cells, generating a rapid type 2 cytokine environment [33].…”

Dendritic cells and cytokines in human inflammatory and autoimmune diseases

“…Studies in mice suggest that DCs might be used in the treatment of autoimmunity through their ability to induce regulatory T cells. Thus, repetitive injections of "semi-mature" DCs induce antigen-specific protection of mice from experimental autoimmune encephalomyelitis and thyroiditis [57,58]. In NOD mice which spontaneously develop diabetes, DCs can induce the generation of Tregs in vitro which provide a therapeutic benefit even after onset of disease [59].…”

“…Recently, the concept that "immature DCs are tolerogenic whereas mature DCs are immunogenic" has been challenged by several studies showing that fully mature DCs can induce tolerance and differentiation of regulatory T cells [57][58][59]. In fact, the integration of different signals by the DCs, including Ag dose, cytokine milieu at sites of inflammation, encountered pathogen etc., will determine whether DCs will become tolerogenic vs. immunogenic.…”