Transcript Generation of ligands for the T cell receptor

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
T
APC
Types of pathogens
2
1
cytosol
“endogenous”
ER
3
Vesicles
Endocytic
vesicles
“exogenous”
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
Endogenous/Cytosolic
Tc
TH
I
TAP
II
APC
TAP: Transporters associated with Ag processing
Exogenous
Intro-vesicular
Two classical pathways of
Ag processing:
• Endogenous (cytosolic) pathway
 “MHC Class I pathway”  Tc cells
• Exogenous (endocytic) pathway
 “MHC Class II pathway”  Th cells
(TAP)
Proteasome & subunit
The Class I pathway
1 2
Empty Class I molecules are unstable
under physiological temperature
TAP deficient (RMA-s)
Normal
Exogenous peptides
(370C)
370C
19 - 330C
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
Ii
CLIP
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
CLIP
HLA-DM
Cytosolic
proteins
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
MHC deficiency
Heterozygotes
b
A
a
b
E
a
Inbred
A1
A B
1 2 1 2
B1
Homozygotes
b
A
a
b
E
A1 B1
A1 B1
a
B1
B1
A1 A1
B1 B1
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 interactions & co-operations
• Cell adhesion molecules
• Cytokines and cytokine receptors
Question:
Chances of the specific T cell:APC interactions ?
(1)
(3)
(2)
Organized
distribution
F
(B + FDC)
GC
+ DC
T: T cell area
B: B cell area
F: B cell follicle
GC: germinal centre
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
Lymph node cortex
(3)
HEV
Endothelium
CD34 Glycam 1
ICAMs
LFA-1
L-Selectin
T
(1)
HEV: high endothelial venue
T
(2)
T cell:APC interactions
Armed effector T cells are guided to sites of infection
by newly expressed adhesion molecules
Cytokines
- Small pharmacologically active products of cells
- Nomenclature & classification
• 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)
Chemokines & Chemokine receptors
Chemokine Group
Examples
Target cells
Receptors
CXC
IL-8
Mig, IP-10
neutrophils
activated T
CXCR1, 2
CXCR3
CC
MIP-3b
DC-CK1,
MDC
naïve T
naïve T
DC, T, NK
CCR7
?
CCR4
C & CX3C
Fractalkine
T, mono., neutr.
CX3CR1
6-Cysteine CC
6Ckine
T, B, mesangial
?
ELR+
ELR-
*ELR: Cysteine residues ‘Glu-Leu-Arg’
g
IL-2Ra (CD25)
- Cell activation marker
T cell activation and proliferation
(high affinity)
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