1. Introduction to Immunology
Jianzhu Chen
Department of Biology
Massachusetts Institute of Technology
Principles of adaptive immunity
TCR recognition
Antigen presentation and processing
Host defense against viruses

2. Innate immunity: Preformed, non-specific effectors.
Adaptive immunity: Immune mechanisms that are mediated by T and B lymphocytes and that change in response to infection.
Innate
Adaptive
Cells
Ag receptors
Ag recognition
Speed
Memory

3. Principle of the Adaptive Immunity
What is fundamental challenge faced by the immune system?
Fact:
Strategy:
Solution:

4. What are the consequences of using V(D)J recombination to create antigen receptor diversity?

5. Antigen-presenting cells (APC)
Key molecules and cells of the adaptive immunity
3 molecules
3 cell types
4 cardinal features a V
B cells
T cells
Antigen-presenting cells (APC)
Dendritic cells (DC)
Macrophage
B cells

6. Antigen recognition
by BCR and TCR

7. TCR-peptide-MHC
(pMHC) interaction

8. MHC Structure
Wiley et al. 1987
peptide
Kuby 7-10

9. TCR-pMHC interaction Extensive contacts: between TCR and peptide
between TCR and MHC
TCR molecules are evolved to bind to MHC

10. TCR-pMHC interaction

11. Major Histocompatibility Complex (MHC)
1930s: Peter Gorer identified four groups (I, II, III, and IV) of blood cell antigens in inbred mice.
1950s: George Snell established the group II antigens mediate rejection of transplanted tumors and other tissues.
Histocompatibility antigens (H-2 in mouse)
Human Leukocyte Antigens (HLA in human)

12. MHC type determine the ability of T cell response.
MHC Restriction
MHC type determine the ability of T cell response.
Zinkernagel & Doherty, 1975

13. MHC Structure Similar to Ig and TCR, belongs to the Ig superfamily a
Kuby 4-20

14. Two compartments of the cell

15.  + 2m (2 microglobulin)
MHC Structure
Class I
 + 2m (2 microglobulin)
Simplified:
Model: 1 2 3
2m
peptide
Class II
 +  subunits 1 2 1 2
peptide L a2 a1 a3 Tm C
Gene:
Peptide-binding proteins
Peptide is part of the stable structure (heterotrimers)

16. MHC Structure
Class I
b2m
Class II
Peptide
binding
cleft

17. MHC Structure Class I Class II Peptide binding domain 1 / 2 1 / 1
Peptide binding cleft
Closed at both ends
Open
Kuby 7-10

18. MHC Structure Class I Class II Peptide binding domain 1 / 2 1 / 1
Peptide binding cleft
Closed at both ends
Open
Length of peptide
8-10
13-15 (hanging out)
Kuby 7-12

19. MHC Structure Class I Class II Peptide binding domain 1 / 2 1 / 1
Peptide binding cleft
Closed at both ends
Open
Length of peptide
8-10
13-15 (hanging out)
p-MHC interaction
Anchor residues 2 & 9
No anchor residue
Cell
MHC
Denature
Peptide
mass spectrometry
Peptide Sequence

20. MHC Structure Class I Class II Peptide binding domain 1 / 2 1 / 1
Peptide binding cleft
Closed at both ends
Open
Length of peptide
8-10
13-15 (hanging out)
p-MHC interaction
Anchor residues 2 & 9
No anchor residue

21. TCR-pMHC interaction

22. MHC Structure Class I Class II Peptide binding domain 1 / 2 1 / 1
Peptide binding cleft
Closed at both ends
Open
Length of peptide
8-10
13-15 (hanging out)
p-MHC interaction
Anchor residues 2 & 9
No anchor residue
Source of peptide
Cytosolic (endogenous)
Endocytic (exogenous)

23. MHC Structure Class I Class II Peptide binding domain 1 / 2 1 / 1
Peptide binding cleft
Closed at both ends
Open
Length of peptide
8-10
13-15 (hanging out)
p-MHC interaction
Anchor residues 2 & 9
No anchor residue
Source of peptide
Cytosolic (endogenous)
Endocytic (exogenous)
Expression
All nucleated cells
Antigen presenting cells (DC, B, MO)

24. MHC Structure Class I Class II Peptide binding domain 1 / 2 1 / 1
Peptide binding cleft
Closed at both ends
Open
Length of peptide
8-10
13-15 (hanging out)
p-MHC interaction
Anchor residues 2 & 9
No anchor residue
Source of peptide
Cytosolic (endogenous)
Endocytic (exogenous)
Expression
All nucleated cells
Antigen presenting cells (DC, B, MO)
T cell recognition
CD8 (Cytolytic)
CD4 (T helper)

25. MHC Nomenclature Class I Class II HLA-A -B -C HLA-DP -DQ -DR Human
Leukocyte
Antigen
Example: HLA-A2 (or A2), human MHC class I A molecule, allele 2
Mouse
H2-IA
-IE
H2-K -D -L
Haplotype: each set of alleles
H2-Kd (Kd) IAd
Balb/c  H-2d H2-Dd (Dd) IEd
H2-Ld (Ld)

26. MHC Function
How can a small number of MHC molecules present a large number of peptides for TCR recognition?
Polygenic
HLA-C
HLA-B
HLA-A DR 1a 3b 2a 2b DQ DP
Possible MHC class I combinations in one individual:
2A + 2B + 2C = 6

27. MHC Function
How can a small number of MHC molecules present a large number of peptides for TCR recognition?
Polygenic
Polymorphic
Presence of multiple alleles at a given locus within a species
HLA-C
HLA-B
HLA-A DR 1a 3b 2a 2b DQ DP
240
470
110 2 20
350 45 19 89
Possible MHC class I combinations in the human population:
470 x 110 x 240 = 1,240,800

28. MHC Function
How can a small number of MHC molecules present a large number of peptides for TCR recognition?
Polygenic
Polymorphic
Differences in amino acids are concentrated in the peptide-binding groove.
Different MHC molecules bind to different set of peptides
Extremely polymorphic
5%  20 a.a.

29. MHC Function
How can a small number of MHC molecules present a large number of peptides for TCR recognition?
Polygenic
Polymorphic
Co-expression
Presentation of multiple peptides per MHC molecule
>2,000 peptides per class I molecule
>> 2,000 peptides per class II molecule
~105 molecules per cell
HLA-C
HLA-B
HLA-A DR 1a 3b 2a 2b DQ DP
240
470
110 2 20
350 45 19 89