1. Pathogen invasion MM Neutrophil DC PRR Naïve T cell CTL IFN-  B cell IgG IL-4, IL-5, IL-6 Th1 Th2 IgE IgA Cell lysis Tr cell IL-1 , TNF- , chemokines Type 1 /Pro- inflammatory response Inflammation Tissue damage (Autoimmunity) Eosinophil recruitment Type 2 responses Inflammation Tissue damage (Allergic reactions) Fig. 1

2. Tr1 CD8 Tr Th3 Natural Tr cells Inducible Tr cells CD4 + CD25 + FoxP3 + Naïve CD4+CD25 - Thymus Antigen (foreign or self) Naïve CD8 + CD25 - Fig. 2

3. Tr1 CD8 Tr Th3 CTLA-4 Natural Tr cells Inducible Tr cells CD4 + CD25 + Fox3P + IL-10/TGF-   Proliferation  Proliferation  Proliferation  CTL activity  IFN-   IL-4  IFN-  cell-to-cell contact ? CD25 - Fox3P Th2 CD8 APC  CD80/CD86  APC function  Inflammatory cytokines APC Th1 APC MHC- peptide TCR CD28 CD80/CD86 Fig. 3

4. IL-10 / TGF-  Tr IL-10, TGF-  IL-4, IL-5, IL-6 IL-10, IL-13 Th2 ? IL-4, IL-6 IL-12 IFN-  Th1 MØ IL-12, IL-27 IL-1 , TNF-  Type 1 responses Pro-inflammatory Immunity to intracellular pathogens (Autoimmune diseases) Type 2 responses Immunity to extracellular pathogens (Allergy) Th1 cell promoting pathogen molecules (TLR ligands, e.g. LPS, CpG, viral RNA) TLRs Th2 promoting pathogen molecules (helminth products, yeast hyphae, CT, LT, TLR2 ligands) Tr1/Th3 cell promoting pathogen molecules (FHA, CyaA, CT, HCV-NS4, PS +/- TLR ligands) CD11b/CD18, GM1 PRRs TLRs Immune Regulation Anti-inflammatory responses Semi-mature DC CD80 + CD40 - Mature DC CD80 +, CD86 +, CD40 + Mature DC CD86 +, OX40 + Fig. 4