1. 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

2. 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

3. 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

4. Question: How is a TCR ligand generated?

5. Ag processing & presentation
APC

6. Types of pathogens “endogenous” “exogenous” 1 2 3 cytosol Vesicles
Endocytic
vesicles ER
“endogenous”
“exogenous”

7. Types of pathogens or antigens:
Cytosolic - “endogenous”
- viruses, intracellular bacteria
Endocytic/vesicular - “exogenous”
- Intra-vesicular bacteria, parasite etc.
- Extra-cellular pathogens, toxins

8. 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

9. Ag processing & presentationTH Tc
Exogenous
Endogenous/Cytosolic I II
TAP
APC
Intro-vesicular
TAP: Transporters associated with Ag processing

10. Two classical pathways of Ag processing:
Endogenous (cytosolic) pathway
 “MHC Class I pathway”  Tc cells
Exogenous (endocytic) pathway
 “MHC Class II pathway”  Th cells

11. (TAP)
Proteasome & subunit

12. The Class I pathway

13. 1 2

14. Empty Class I molecules are unstable under physiological temperature
TAP deficient (RMA-s)
Normal
Exogenous peptides
(370C)
370C C

15. Empty MHC class I molecule come out in the cold By Ljunggren HG et al
Empty MHC class I molecule come out in the cold By Ljunggren HG et al. Nature (1990) 346:476-80

16. 3

17. The Class II pathway Ii
CLIP

18. 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

19. CLIP
HLA-DM

21. Cytosolic
proteins
proteasome
peptides
TAP

22. 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

23. MHC deficiency Heterozygotes Inbred Homozygotes A E A1 B1 A B A1 B1
A1 B1
A1 B1
A E
b a b a B1
A1 A1
B1 B1

24. Student Q2: ‘Self’ MHC restriction?

25. T cells recognize “self” MHC

26. The environment in which the T cells mature determines
the MHC restriction of the mature T cell receptor repertoire

27. Cell interactions & co-operations
Cell adhesion molecules
Cytokines and cytokine receptors

28. Question: Chances of the specific T cell:APC interactions ?

29. (1)
(3)
(2)

30. Organized distribution T: T cell area B: B cell areaF
+ DC
(B + FDC)
T: T cell area
B: B cell area
F: B cell follicle
GC: germinal centre GC

31. Question How do cells know where to go and act ?

32. 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

33. T cell-endothelium interactions
Lymph node cortex
(3)
HEV
Endothelium
CD34 Glycam 1
ICAMs
LFA-1
L-Selectin T T
(1) (2)
HEV: high endothelial venue

34. T cell:APC interactions

35. Armed effector T cells are guided to sites of infection by newly expressed adhesion molecules

37. Cytokines Small pharmacologically active products of cells
Nomenclature & classification
Lymphokines: produced by lymphocytes
Interleukins: interleukin (IL-1 – IL-26)
interferons, TNF etc.
Monokines: produced by monocytic/phagocytes
Chemokines: CXC (IL-8), CC (DC-CK, MDC), CX3C (Fractalkine)

38. Chemokines & Chemokine receptors
Chemokine Group Examples Target cells Receptors
CXC ELR+ IL-8 neutrophils CXCR1, 2
ELR- Mig, IP-10 activated T CXCR3
CC MIP-3b 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’

42. g
IL-2Ra (CD25)
- Cell activation marker

43. T cell activation and proliferation
(high affinity)

44. Summary 1 Two types of pathogens/Ags:
Cytosolic - “endogenous”
- viruses, intracellular bacteria
Endocytic/vesicular - “exogenous”
- Intra-vesicular bacteria, parasite etc.
- Extra-cellular pathogens, toxins

45. 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)

46. 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

47. 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