Research Report - Nikolaus-Fiebiger-Zentrum für Molekulare Medizin

Targeting antigens under immunizing conditions induced a strong prolonged
proliferative response in either CD4 transgenic T cells (targeting CD11c + CD8 - with
33D1-Ova) or CD8 transgenic T cells (targeting of CD11c + CD8 + DCs with DEC205-
Ova). On the other hand when we targeted antigens under tolerizing conditions
transgenic T cells started to proliferate till day 3, but were deleted afterwards. Left T
cells clearly were of regulatory T cell phenotype (Yamazaki et al., 2008). We further
could show by 2-Photon microscopy that T cells that were interacting with DCs that
presented the antigen under tolerizing conditions or presented the antigen under
immunizing conditions were behaving very similar in dependency on interaction time,
velocity and activation markers expressed on the T cells (Lindquist et al., 2004;
Shakhar et al., 2005). Regarding the induced immune responses we induced under
immunizing conditions with anti CD40 antibody, as gold standard activation stimulus,
we found that targeting antigens to CD11c + CD8 - DCs predominantly induced a TH2 T
cell response when we analyzed Balb/c mice but on the other hand a TH1 T cell
response when CD11c + CD8 + DCs were targeted (Soares et al., 2007).
Altogether, our data indicate that targeting of CD11c + CD8 + DCs by anti-
DEC205 antibody seems to be an efficient way to induce cross presentation in the
classical MHCI pathway. In contrast, CD11c + CD8 - DCs preferentially processed and
presented antigens in the traditional MHCII pathway. Currentlc we are investigating
the antigen processing machineries when DCs were activated with TLR ligands.
Analysis of early T cell tolerance and T cell immunity
Diana Dudziak, Kirsten Neubert
We and others could show that antigen targeted DCs elicited a peripheral tolerance
in antigen-specific T cells under non-inflammatory conditions. In contrast, delivery of
recombinant antigen-carrying antibodies together with a stimulatory anti CD40
antibody established an antigen-specific immune response. Because of severe side
effects such as systemic inflammation and the non-specific activation of all immune
cells that express CD40 on their cell surface the usage of systemic anti CD40
antibody cannot be a feasible costimulatory strategy for human therapy.
As TLR stimulation is an approach already used in clinical trials we believe that TLR
stimulation in combination with our antibody targeting strategy might be an alternative
approach to induce protective immune responses in vivo. TLRs are very well
characterized class of pattern-recognition-receptors (PRRs) in mammalian species.
The TLRs are differentially expressed on various cells of the immune system
including DCs. TLRs 1, 2, 4, 5, and 6 are expressed on the cell surface and seem to
have evolved to recognize bacterial products. In contrast TLRs 3, 7, 8, and 9 are
expressed intracellularly in endosomes and lysosomes and recognize nucleic acids.
Several pathogen-associated molecules such as double stranded RNA (poly(I:C) =
pIC), bacterial or viral double stranded DNA (CpG), bacterial lipopolysaccharides
(LPS), lipoproteins (Pam3Cys = Pam3), lipoteichoide acids, zymosan, or flagellin
have been identified to bind to TLR receptors resulting in a strong inflammatory and
protective immune response.
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