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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 by MHC– Genetic basis
– Polygeny– Polymorphism
– Structural basis– MHC polymorphic binding pockets– Peptide anchor residues
• Types of APC– Target cell– Professional APC
Student Q1: What cells express MHC molecules:
Class I, Class II or both, & why?
• 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
• Cell interactions & co-operation
Question:
How is a TCR ligand generated?
Ag processing & presentation
APC
T
Types of pathogens
cytosolER
Vesicles Endocytic vesicles
“exogenous”“endogenous”
1 2 3
Types of pathogens or antigens:
• Cytosolic - “endogenous” - viruses, intracellular bacteria
• Endocytic/vesicular - “exogenous”- Intra-vesicular bacteria, parasite etc.- Extra-cellular pathogens, toxins
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)
• Vaccine design: Types of immune responses:- Humoral (B) endocytic pathway - Cell-mediated (CTL) cytosolic pathway
• MHC deficiencies: - Congenital MHC class II deficiency - Ir gene defects
Heterozygotes
Inbred
Homozygotes
A B
A1 B1 A1 B1
B1 B1A1 A1
A E
1 2 1 2
A E
A1
B1
B1
B1
MHC deficiency
Student Q2:
‘Self’ MHC restriction?
T cells recognize “self” MHC
The environment in which the T cells mature determines the MHC restriction of the mature T cell receptor repertoire
• Cell adhesion molecules
• Cytokines and cytokine receptors
Cell interactions & co-operations
Question:
Chances of the specific T cell:APC interactions ?
(1)
(2)(3)
+ DC
GC
(B + FDC)F
T: T cell areaB: B cell area
F: B cell follicleGC: germinal centre
Organizeddistribution
Question
How do cells know where to go and act ?
Adhesion molecules:
SELECTINS - e.g. L-selectin, P-selectin, E-selectin MUCIN-LIKE MOLECULES - (Addressins) e.g. CD34 INTEGRINS - e.g. LFA-1, VLA-4 IMMUNOGLOBULIN SUPERFAMILY - e.g. CD2 (LFA-2), ICAM-1, 2, 3
T cell-endothelium interactions
T T
Lymph node cortex
HEV
LFA-1L-Selectin
CD34 Glycam 1 ICAMs
Endothelium
(1) (2)
(3)
HEV: high endothelial venue
T cell:APC interactions
Armed effector T cells are guided to sites of infection by newly expressed adhesion molecules
Cytokines
• Lymphokines: produced by lymphocytes
• Interleukins: interleukin 1 - 26 (IL-1 – IL-26)
interferons, TNF etc.
• Monokines: produced by monocytic/phagocytes
• Chemokines: CXC (IL-8), CC (DC-CK, MDC), CX3C (Fractalkine)
- Small pharmacologically active products of cells
- Nomenclature & classification
Chemokines & Chemokine receptors
Chemokine Group Examples Target cells Receptors
CXC ELR+ IL-8 neutrophils CXCR1, 2ELR- Mig, IP-10 activated T CXCR3
CC MIP-3 naïve T CCR7
DC-CK1, naïve T ? MDC DC, T, NK CCR4 C & CX3C Fractalkine T, mono., neutr. CX3CR1
6-Cysteine CC 6Ckine T, B, mesangial ?
*ELR: Cysteine residues ‘Glu-Leu-Arg’
IL-2R (CD25)- Cell activation marker
(high affinity)
T cell activation and proliferation
Summary 1
Two types of pathogens/Ags:
• Cytosolic - “endogenous” - viruses, intracellular bacteria
• Endocytic/vesicular - “exogenous”- Intra-vesicular bacteria, parasite etc.- Extra-cellular pathogens, toxins
Summary 2
Two classical pathways for Ag processing
• “MHC class I pathway” CD8+ T cells (Endogenous/cytosolic, TAP-dependent pathway)
• “MHC class II pathway” CD4+ T cells(Exogenous/endocytic, TAP-independent pathway)
Summary 3
• A defect or defects in Ag processing or presentation may result in severe immunological consequences
• Pathogens may evade host immune system by interfering with the mechanisms of Ag processing and presentation
• Cells of the immune system interact in a complex network
• Cell interactions and re-circulation are mediated by adhesion molecules, cytokines and cytokine receptors
Summary 4 Cytokines - principles of action
• Local & systemic effects
• Unique receptor for each cytokine
• Pleiotropic
• Synergistic & autocrine fashion
• Complex network – a single cell can secrete, or be susceptible to, more than one cytokine
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