Institute t of Experimental Immunology University of Bonn, Germany

Transcription

1 How T cells recognize antigen Christian Kurts Institute t of Experimental Immunology University of Bonn, Germany

2 When do T cells recognize antigen? Antigen uptake Activation phase 1st recognition Effector phase 2nd recognition T cell memory

3 How do T cells recognize antigen?

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5 Why do T cells have to recognize antigen? CD4 + T cells help immune effectors To target their effector function! CD8 + T cells kill virus-infected infected and malignant cells

6 Why do T cells have to recognize antigen? To target their effector function! CD4 + T cells CD4 + T cells interact with help immune other immune cells effectors CD8 + T cells kill virus-infected infected and malignant cells CD8 + T cells principally have to be able to interact with all body cells

7 Why do T cells have to recognize antigen? To target their effector function! CD4 + T cells CD4 + T cells interact with help immune other immune cells effectors I expressed by immune cells CD8 + T cells kill virus-infected infected and malignant cells CD8 + T cells principally have to be able to interact with all body cells on all body cells

8 Pathways of antigen presentation 1. Exogenous way 2. Endogenous way 3. Cross-presentation professional APC MHC class I + cell cross-presenting DC endogenous antigen I exogenous antigen exogenous antigen CD4 + Tcell CD8 + Tcell CD8 + Tcell

9 Mechanisms of Endocytosis Phagocytosis Pinocytosis Receptor-mediated endocytosis

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11 Figure 1-29

12 Pathways of antigen presentation 1. Exogenous way 2. Endogenous way 3. Cross-presentation professional APC MHC class I + cell cross-presenting DC endogenous antigen I exogenous antigen exogenous antigen CD4 + Tcell CD8 + Tcell CD8 + Tcell

13 Purpose of the endogenous pathway: it allows CTL to detect t intracellular l viruses 1. Exogenous way 2. Endogenous way professional APC MHC class I + cell CTL kill only virus-infected or malignant cells I exogenous antigen professional APCs that have endocytosed viral debris are not killed CD4 + Tcell CD8 + Tcell

14 Figure 5-6

15 Pathways of antigen presentation 1. Exogenous way 2. Endogenous way 3. Cross-presentation professional APC MHC class I + cell cross-presenting DC endogenous antigen I exogenous antigen exogenous antigen CD4 + Tcell CD8 + Tcell CD8 + Tcell

16 Why do we need cross-presentation? Naive CD8 T cells B7 CD28 MHC... recirculate through secondary lymphatics, require costimulatory molecules Activated CD8 T cells (CTLs) MHC... can infiltrate non-lymphoid tissues, don t depend on costimulatory molecules

17 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?

18 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 Myeloid CD11c+ CD4+ CD8- CD205+ CD11b+?? Langer-...hans CD11c+ CD4+ CD8+ CD205+CD11b+ Langerin+ Transports Ag in skin-draining LNs Shortman and Liu, Nature Reviews Immunology, 2002 Plasma- cytoid B220+ Gr-1+ CD90+ CD11c lo CD4+ CD8- CD205- CD11b- produce IFNα in viral infections TIP CD11c+ CD4- CD8- CD205- CD11b INT make TFNα and NO in bacterial infection CD103+ CD11c+ CD8lo CD Langerin+ Cross-presenting + migratory

19 Cross-presentation Heath & Carbone, Nature Reviews Immunology, 2001

20 Cross-presentation occurs in phagosomes/endosomes, not in the ER CD8 T cell Protea asome TAP Houde et al, Nature 2003 Burgdorf et al, Nature Immunol, 2008

21 Trf-US6 inhibits cross-presentation TrfR US6-Trf TAP TAP TAP ER

22 Trf-US6 inhibits cross-presentation but not endogenous antigen presenation TrfR US6-Trf TAP TAP TAP ER

23 The MR introduces OVA into a distinct stable early endosomal compartment where cross-presentation occurs Burgdorf et al., Nature Immunology, 2008 CD8 T cell CD8 T cell Proteasom TAP TAP ER

24 Cross-presentation avoids viral subversion of antigen presentation 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, antigen presentation not impaired

25 Summary: Cross-Presentation activation of naive CD8 + T cells by dendritic cells in draining lymph nodes allows naive CD8 + T cells to efficiently scan non-lymphoid tissues for pathogens without leaving the lymphatic compartment Cross-presenting DC ti ti f i CD8 + T ll b d d iti CD8 + T cell exogenous antigen Ensures antigen presentation with costimulation avoids escape from antigen presentation is important for immunity against viruses restricted to non-lymphoid tissues (Cross-Priming) Pi i maintains tolerance against self antigens by bcl-2-inhibitable apoptosis (Cross-Tolerance) Restricted to distinct DCs (in mice CD8+)