Summary of the last lecture • Features of T cell antigen recognition – APC – Ag processed – MHC restrictions – TCR ligand: Peptide + MHC • Basis for Ag presentation by MHC – Genetic basis – Polygeny – Polymorphism – Structural basis – MHC polymorphic binding pockets – Peptide anchor residues • Types of APC – Target cell
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Summary of the last lecture Features of T cell antigen recognition –APC –Ag processed –MHC restrictions –TCR ligand: Peptide + MHC Basis for Ag presentation.
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Summary of the last lecture
• Features of T cell antigen recognition– APC– Ag processed– MHC restrictions– TCR ligand: Peptide + MHC
• Virtually all nucleated cells express MHC Class I • Potentially infectable (e.g. by virus) as target cells (for Tc)
• Thymic stromal cells express both • T cell selection –thymic education
• Key immune cells express both• B cells: present Ag to Th to receive help for Ab responses• MQ: first line of defense, once activated ‘professional’ APC• DC: initiation of immune responses ‘true professional’ APC
Pathways of Ag processing,Ag presentation & co-stimulations
• Types of pathogens & Ags
• Two classical pathways for Ag processing
• Ag processing, presentation, & their clinical relevance
Two major subsets of T cells whose recognition of antigens are restricted by
two different classes of MHC:
• CD8+ T cell (cytotoxic T)- MHC Class I restricted
• CD4+ T cell (T helper)- MHC Class II restricted
Ag processing & presentation
APC
Tc Exogenous
Endogenous/CytosolicI II
Intro-vesicular
TAP
TAP: Transporters associated with Ag processing
TH
Two classical pathways of Ag processing:
• Endogenous (cytosolic) pathway “MHC Class I pathway” Tc cells
• Exogenous (endocytic) pathway “MHC Class II pathway” Th cells
Proteasome & subunit
(TAP)
The Class I pathway
1 2
Empty Class I molecules are unstable under physiological temperature
Exogenous peptides
370C 19 - 330C
Normal TAP deficient (RMA-s)
(370C)
Empty MHC class I molecule come out in the
cold
By Ljunggren HG et al.
Nature (1990) 346:476-80
3
The Class II pathway
CLIP
Ii
Functions of the Invariant Chain (Ii)
• Block MHC Class II molecules from binding of peptides derived from endogenous antigens
• Direct MHC Class II molecule to cellular vesicles where exogenous peptides are generated
HLA-DM
CLIP
Cytosolicproteins
proteasome
peptides
TAP
Ag processing, presentation & their clinical relevance
• Pathogen strategies for immune evasion:- prevent TAP function (HSV)- inhibit endosomal acidification (Helicobacter pylori)- retention of MHC molecules (Retroviruses)