Repetitive Injections of Dendritic Cells Matured with Tumor Necrosis Factor α Induce Antigen-specific Protection of Mice from Autoimmunity

Abstract

Mature dendritic cells (DCs) are believed to induce T cell immunity, whereas immature DCs induce T cell tolerance. Here we describe that injections of DCs matured with tumor necrosis factor (TNF)-α (TNF/DCs) induce antigen-specific protection from experimental autoimmune encephalomyelitis (EAE) in mice. Maturation by TNF-α induced high levels of major histocompatibility complex class II and costimulatory molecules on DCs, but they remained weak producers of proinflammatory cytokines. One injection of such TNF/DCs pulsed with auto-antigenic peptide ameliorated the disease score of EAE. This could not be observed with immature DCs or DCs matured with lipopolysaccharide (LPS) plus anti-CD40. Three consecutive injections of peptide-pulsed TNF/DCs derived from wild-type led to the induction of peptide-specific predominantly interleukin (IL)-10–producing CD4+ T cells and complete protection from EAE. Blocking of IL-10 in vivo could only partially restore the susceptibility to EAE, suggesting an important but not exclusive role of IL-10 for EAE prevention. Notably, the protection was peptide specific, as TNF/DCs pulsed with unrelated peptide could not prevent EAE. In conclusion, this study describes that stimulation by TNF-α results in incompletely matured DCs (semi-mature DCs) which induce peptide-specific IL-10–producing T cells in vivo and prevent EAE.

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

“…Fig. 1D) as shown previously [23]. The T. brucei AnTat1.1-derived mfVSG induced minor amounts of IL-12p40 in DCs as compared with TNF-matured DCs.…”

“…Understanding these differences and similarities will be valuable to understand parasitic immune evasion but also for immunotherapy settings where Th2-cell responses act tolerogenic. This has been observed before, especially upon repetitive stimulation of Th2-cell responses characterized by increasing numbers of regulatory IL-10-producing T (Tr1) cells as a tolerance mechanism [29,30].Indeed, repetitive injections of TNF-matured DCs prevented the induction of the autoimmune disease EAE mediated at least in part by IL-10 1 CD4 1 T cells [23]. Later, other autoimmune diseases such as thyroiditis and arthritis were also prevented by the application of TNF-matured DCs [31,32].…”

“…Mice develop MOG-reactive [23,33]. We therefore wanted to analyze how the partial DC maturation stages induced by TLR-dependent or independent stimuli would modulate the autoimmune disease EAE.…”

“…Mice develop MOG-reactive [23,33]. We therefore wanted to analyze how the partial DC maturation stages induced by TLR-dependent or independent stimuli would modulate the autoimmune disease EAE.To detect whether the DC injections ameliorate or worsen the disease, we switched the amounts per DC injection from 3 to 3.5 Â 10 6 cells, which is the fully protective protocol [23,33,44] to 2-2.5 Â 10 6 cells, which leads to about 50% reduced clinical score [44]. Three i.v.…”

“…Others have addressed this question before by using CpG-matured BM-DCs, which are similar to LPS for the instruction of Th1-cell responses, but without effects on asthma [69]. Lambrecht's group has shown that rather plasmacytoid DCs may be able to control asthma [70,71].Semi-mature DCs prevented the paralyzing symptoms in the EAE model by immune deviating toward a Th2/Tr1 protective response, whereas LPS-matured DCs were not protective [33,72,73]. However, the application of semi-mature DCs in Th2-cell associated asthma model neither ameliorated nor worsened the disease symptoms, similarly to the previous data obtained for the murine L. major Th2-cell infection model [34].…”