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Introduction to Immunology
Jianzhu Chen
Department of Biology
Massachusetts Institute of Technology
[email protected]
• Principles of adaptive immunity
• TCR recognition
• Antigen presentation and processing
• Host defense against viruses
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
Cells
Ag receptors
Ag recognition
Speed
Memory
Adaptive
Principle of the Adaptive Immunity
What is fundamental challenge faced by the immune system?
Fact:
Strategy:
Solution:
What are the consequences of using V(D)J
recombination to create antigen receptor diversity?
Key molecules and cells of the adaptive immunity
V
3 molecules
3 cell types
4 cardinal features
V
V
a
V
B cells
V
T cells
Antigen-presenting cells (APC)
Dendritic cells (DC)
Macrophage
B cells
Antigen recognition
by BCR and TCR
TCR-peptide-MHC
(pMHC) interaction
MHC Structure
Wiley et al. 1987
peptide
TCR-pMHC interaction
Extensive contacts:
between TCR and peptide
between TCR and MHC
TCR molecules are evolved to bind to MHC
TCR-pMHC interaction
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)
MHC Restriction
MHC type determine the
ability of T cell response.
Zinkernagel & Doherty, 1975
MHC Structure
Similar to Ig and TCR, belongs to the Ig superfamily
a
Two compartments of the cell
MHC Structure
Class I
Class II
a + 2m (2 microglobulin)
a +  subunits
peptide
Model:
peptide
a2
a1
a1
1
a3
 2m
a2
2
Simplified:
Gene:
L
a1
a2
a3 Tm C C
Peptide-binding proteins
Peptide is part of the stable structure (heterotrimers)
MHC Structure
Class I
Class II
Peptide
binding
cleft
Peptide
binding
cleft
2m
MHC Structure
Peptide binding
domain
Peptide binding
cleft
Class I
Class II
a1 / a2
a1 / 1
Closed at both ends Open
MHC Structure
Peptide binding
domain
Peptide binding
cleft
Length of peptide
Class I
Class II
a1 / a2
a1 / 1
Closed at both ends Open
8-10
13-15 (hanging
out)
MHC Structure
Class I
Class II
Peptide binding
domain
a1 / a2
a1 / 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
MHC Structure
Class I
Class II
Peptide binding
domain
a1 / a2
a1 / 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
TCR-pMHC interaction
MHC Structure
Class I
Class II
Peptide binding domain a1 / a2
a1 / 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)
MHC Structure
Class I
Class II
Peptide binding
domain
a1 / a2
a1 / 1
Peptide binding
cleft
Length of peptide
Closed at both ends Open
8-10
13-15 (hanging out)
p-MHC interaction Anchor residues 2
&9
No anchor residue
Source of peptide
Endocytic
(exogenous)
Antigen presenting
cells (DC, B, MO)
Expression
Cytosolic
(endogenous)
All nucleated cells
MHC Structure
Peptide binding
domain
Peptide binding
cleft
Length of peptide
Class I
Class II
a1 / a2
a1 / 1
Closed at both ends Open
8-10
13-15 (hanging out)
p-MHC interaction Anchor residues 2
&9
Source of peptide
Cytosolic
(endogenous)
No anchor residue
Expression
All nucleated cells
T cell recognition
CD8 (Cytolytic)
Antigen presenting
cells (DC, B, MO)
CD4 (T helper)
Endocytic
(exogenous)
MHC Nomenclature
Human
Human
Leukocyte
Antigen
Class I
HLA-A
-B
-C
Class II
HLA-DP
-DQ
-DR
Example: HLA-A2 (or A2), human MHC class I A molecule, allele 2
Mouse
H2-K
-D
-L
Haplotype: each set of alleles
H2-Kd (Kd)
Balb/c  H-2d
H2-Dd (Dd)
H2-Ld (Ld)
H2-IA
-IE
IAd
IEd
MHC Function
How can a small number of MHC molecules present a
large number of peptides for TCR recognition?
DQ
3 2a
DR
3 1a
Possible MHC class I combinations in one individual:
2A + 2B + 2C = 6
HLA-A
DP
2 2a
HLA-B
HLA-C
• Polygenic
MHC Function
How can a small number of MHC molecules present a
large number of peptides for TCR recognition?
89 19
DQ
3 2a
DR
3 1a
45 20 350 2
HLA-A
DP
2 2a
Presence of multiple alleles at a given locus
within a species
HLA-B
HLA-C
• Polygenic
• Polymorphic
470 110
240
Possible MHC class I combinations in the human population:
470 x 110 x 240 = 1,240,800
MHC Function
How can a small number of MHC molecules present a
large number of peptides for TCR recognition?
• Polygenic
• Polymorphic
Extremely polymorphic
5%  20 a.a.
Differences in amino
acids are concentrated
in the peptide-binding
groove.
Different MHC molecules bind to different set of peptides
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
89 19
DQ
3 2a
DR
3 1a
45 20 350 2
HLA-A
DP
2 2a
HLA-B
HLA-C
>2,000 peptides per class I molecule
>> 2,000 peptides per class II molecule
~105 molecules per cell
470 110
240