Practical Solution: presentation to cytotoxic T cells. How dendritic cells present antigen. How dendritic cells present antigen

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1 Christian Kurts Institutes of Molecular Medicine and Experimental Immunology University of Bonn, Germany - presentation and (CTL) activation - I presentation and CD4 + T cell (Th cell) activation Different types of T cells defend us against different pathogens T cells have a unique T cell receptor = they are -specific NKT cells s kill virus-infected and malignant cells Recognize lipid s Distinct bacteria CD4 + T cells help immune effectors How are virus-infected cells detected? T cells recognize peptides from bound to MHC Molecules How to detect intracellular viruses? Practical Solution: Display representative samples of intra-cellularly produced proteins MHC on I-restricted the cell surface presentation to cytotoxic T cells scan these; if virus-s are found, kill the cells Eric Reits 1

2 MHC structure Anchor residues Falk K,... Rammensee HG, Nature MHC explains autoimmunity susceptibility 2

3 MHC explains transplant rejection - presentation and (CTL) activation - I presentation and CD4 + T cell (Th cell) activation Mechanism of presentation Figure 5-6 Eric Reits Figure presentation and CD8+ T cell (CTL) activation - I presentation and CD4 + T cell (Th cell) activation 3

4 Activation of T helper cells Eric Reits Pathways of presentation 1. Endogenous way MHC class I + cell endogenous 2. Exogenous way professional APC I CD4 + T cell - presentation and (CTL) activation - I presentation and CD4+ T cell (Th cell) activation Ralph M. Steinman, Nobel laureate 2011 Dendritic cells How are ic peptides presented to T cells? Steinman & Cohn, J Exp Med

5 Signals 1, 2 and 3 in T cell activation The CTL immune response - presentation and (CTL) activation - I presentation and CD4+ T cell (Th cell) activation Antigen uptake Activation phase Effector phase Why do we need cross-presentation? Pathways of presentation What if a virus does not infect DC? What if a tumor does not infect DCs? What about vaccination? 1. Endogenous way MHC class I + cell 2. Exogenous way professional APC 3. Cross-presentation cross-presenting DC If the DC does not express an itself, it needs to endocytose and cross-present it Antigen uptake CTL Activation phase CTL Effector phase endogenous I CD4 + T cell Cross-presentation is necessary in the CTL priming phase 5

6 Cell biology of cross-presentation Cross-presentation occurs in phagosomes/endosomes, not in the ER CD8 T cell TAP Proteasome Houde et al, Nature 2003 Burgdorf et al, Nature Immunol, 2008 Why do we need cross-presentation? If the DC does not express an itself, it needs to endocytose and cross-present it Only some DC subsets cross-present and are killed T helper and B cell responses unaffected Guilliams et al, EJI2010 Antigen uptake CTL Activation phase CTL Effector phase Cross-presentation is necessary in the CTL priming phase If a DC cross-presents, it becomes suceptible to CTL killing cross-presenting DCs are killed too! Does not matter: Cross-primed CTL do not need them any more Biological significance of cross-presentation Summary: Activation of cytotoxic s against: Tumors that do not arise from APCs Viruses that do not infect APCs antiviral vaccines / tumor vaccinations = Cross-Priming Inactivation of autoreactive s: Bim/Fas-mediated, Bcl-2-inhibitable apoptosis Peripheral tolerance Fails in Type 1 Diabetes mellitus = Cross-tolerance cross-presenting DC - T cell responses,t cell receptor, MHC restriction: clonality, diseases, transplant rejection - presentation and (CTL): intracellular s, proteasome, TAP, detection of intracellular microbes s: Perforins, granzymes, FasL, TNF - I presentation and CD4 + T cell (Th cell) activation: early-late endo/phagosomes, acidification, CLIP, DM - T cell activation: DCs: transport, processing, presentation - T cell activation: Signals 1, 2 & 3 : MHC-, costimulation, cytokines - Cross-presentation: activation of CTL, early endo/phagosomes, only some DC subsets cross-present; only these are eventually killed by CTL, 6