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How T cells recognize antigen Christian Kurts IInstitute tit t off Experimental E i t l Immunology I l University of Bonn, Germany When do T cells recognize antigen? Antigen uptake Activation phase Æ1st recognition Effector phase Æ2nd recognition T cell memory How do T cells recognize i antigen? ti ? Why do T cells have to recognize antigen? To target their effector function! CD4+ T cells help immune effectors CD8+ T cells kill virus infected virus-infected and malignant cells Why do T cells have to recognize antigen? To target their effector function! CD4+ T cells help immune effectors Î CD4+ T cells interact with other immune cells CD8+ T cells kill virus-infected virus infected and malignant cells Î CD8+ T cells principally have to be able to interact with all body cells Why do T cells have to recognize antigen? To target their effector function! CD4+ T cells help immune effectors Î CD4+ T cells interact with other immune cells Î MHC II expressed by immune cells CD8+ T cells kill virus-infected virus infected and malignant cells Î CD8+ T cells principally have to be able to interact with all body cells Î MHC I on all body cells Pathways of antigen presentation 1. Exogenous way professional APC 2. Endogenous way MHC class I+ cell 3. Cross-presentation cross-presenting g DC endogenous antigen MHC II TCR MHC I exogenous antigen CD4+ T cell TCR CD8+ T cell MHC I TCR exogenous antigen CD8+ T cell Mechanisms of Endocytosis Phagocytosis Pinocytosis Receptor-mediated endocytosis Figure 1-29 Pathways of antigen presentation 1. Exogenous way professional APC 2. Endogenous way MHC class I+ cell 3. Cross-presentation cross-presenting g DC endogenous antigen MHC II TCR MHC I exogenous antigen CD4+ T cell TCR CD8+ T cell MHC I TCR exogenous antigen CD8+ T cell Purpose of the endogenous pathway: it allows ll CTL to t d detect t t intracellular i t ll l viruses i 1. Exogenous way professional APC 2. Endogenous way MHC class I+ cell Î CTL kill only virus-infected or malignant cells MHC II TCR MHC I exogenous antigen CD4+ T cell TCR CD8+ T cell • professional APCs that have endocytosed viral debris are not killed Figure 5-6 Pathways of antigen presentation 1. Exogenous way professional APC 2. Endogenous way MHC class I+ cell 3. Cross-presentation cross-presenting g DC endogenous antigen MHC II TCR MHC I exogenous antigen CD4+ T cell TCR CD8+ T cell MHC I TCR exogenous antigen CD8+ T cell Why y do we need cross-presentation? p Naive N i CD8 T cells B7 MHC CD28 TCR ... recirculate through secondary lymphatics, require costimulatory molecules Activated A i d CD8 T cells (CTLs) MHC TCR ... can infiltrate non-lymphoid tissues, don‘t depend on costimulatory molecules The problem : 1) Naïve CD8 T cells have to be activated by professional APC, 2) Only cells that synthesize antigen themselves can present antigen to CD8 T cells, ⇒ CTL response possible only against viruses that infect DCs or tumors derived from DCs Cross-presentation is necessary in the CTL priming phase What about killing of cross-presenting DCs? Only some DC subsets cross-present Lymphoid CD11c+ CD4- CD8+ CD205+ CD11b- Resident in lymphatics, CD4+CD8 T cell activ Myeloid CD11c+ CD4- CD8- CD205- CD11b+ Resident, stimulates CD4 T cells Myeloid CD11c+ CD4+ CD8- CD205- CD11b+ Resident in tissues, activates CD4 T cells M l id CD11c+ Myeloid CD11 CD4+ CD4 CD8 CD8- CD205+ CD205 CD11b CD11b+ ?? Langer...hans Transports Ag in skin-draining LNs CD11c+ CD4+ CD8+ CD205+CD11b+ Langerin+ g Shortman and Liu, Nature Reviews Immunology, 2002 Plasmacytoid CD11clo CD4+ CD8- CD205- CD11bB220+ Gr-1+ CD90+ d IFN IFNα in i viral i l iinfections f ti produce TIP CD11c+ CD4- CD8- CD205- CD11bINT make TFNα and NO in bacterial infection CD103+ CD11c+ CD8lo CD103+ - Langerin+ Cross-presenting + migratory Cross-presentation p Heath & Carbone, Nature Reviews Immunology, 2001 Cross-presentation occurs in phagosomes/endosomes, h / d nott in i the th ER CD8 T cell Protea asome MHC I TAP Houde et al, Nature 2003 Burgdorf et al, Nature Immunol, 2008 Trf-US6 inhibits cross-presentation US6-Trf TrfR TAP TAP TAP ER MHC I Trf-US6 inhibits cross-presentation but not endogenous antigen presenation US6-Trf TrfR TAP TAP TAP ER MHC I The MR introduces OVA into a distinct stable early endosomal compartment where cross cross-presentation presentation occurs Burgdorf et al., Nature Immunology, 2008 CD8 T cell CD8 T cell Proteasom MHC I TAP TAP ER MHC I Cross-presentation avoids viral subversion off antigen ti presentation t ti Some virusses (Herpes, Influenza,..) infect APC and interfere with antigen presentation → no CD8 T cell activation Cross-presenting APC takes up viral antigens from infected cells, virus does not replicate in APC APC, antigen presentation not impaired Summary: Cross-Presentation C Cross-presenting ti DC • activation ti ti off naive i CD8+ T cells ll by b dendritic d d iti cells in draining lymph nodes • allows naive CD8+ T cells to efficiently scan non-lymphoid tissues for pathogens without leaving the lymphatic compartment MHC I TCR • Ensures antigen presentation with costimulation • avoids escape from antigen presentation exogenous g antigen • is important for immunity against viruses restricted to non-lymphoid tissues (C (Cross-Priming) Pi i ) CD8+ T cell • maintains tolerance against self antigens by bcl 2 inhibitable apoptosis (Cross-Tolerance) bcl-2-inhibitable (Cross Tolerance) • Restricted to distinct DCs (in mice CD8+)
