Introduction to ImmunologyJianzhu Chen
Department of BiologyMassachusetts Institute of Technology
• Principles of adaptive immunity
• TCR recognition
• Antigen presentation and processing
• Host defense against viruses
Innate Adaptive
Cells
Ag receptors
Ag recognition
Speed
Memory
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.
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?
V
VV
V
V
Key molecules and cells of the adaptive immunity
B cells T cells Antigen-presenting cells (APC)Dendritic cells (DC)
MacrophageB cells
3 molecules3 cell types4 cardinal features
Antigen recognition by BCR and TCR
TCR-peptide-MHC (pMHC) interaction
peptide
MHC Structure Wiley et al. 1987
TCR-pMHC interaction
Extensive contacts:between TCR and peptidebetween 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)
Zinkernagel & Doherty, 1975
MHC Restriction
MHC type determine the ability of T cell response.
MHC StructureSimilar to Ig and TCR, belongs to the Ig superfamily
Two compartments of the cell
Peptide-binding proteinsPeptide is part of the stable structure (heterotrimers)
Class I
+ 2m (2 microglobulin)
Simplified:
Model:
12
3 2m
peptide
Class II
+ subunits
1
2
1
2
peptide
MHC Structure
L 21 3 Tm C CGene:
MHC Structure
Class IIClass I
2m
Peptidebindingcleft
Peptidebindingcleft
Class I Class II
Peptide binding domain
1 / 2 1 / 1
Peptide binding cleft
Closed at both ends Open
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)
MHC Structure
Class I Class IIPeptide 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
MHC Structure
Cell
MHC
Denature
Peptide
mass spectrometry
Peptide Sequence
Class I Class IIPeptide 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
MHC Structure
TCR-pMHC interaction
MHC StructureClass 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)
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)
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)
MHC Structure
MHC Nomenclature
HLA-DP
-DQ
-DR
HLA-A
-B
-C
HumanHuman Leukocyte Antigen
Class IIClass I
Example: HLA-A2 (or A2), human MHC class I A molecule, allele 2
Mouse H2-IA
-IE
H2-K
-D
-LHaplotype: each set of alleles
H2-Kd (Kd) IAd
Balb/c H-2d H2-Dd (Dd) IEd
H2-Ld (Ld)
MHC FunctionHow can a small number of MHC molecules present a large number of peptides for TCR recognition?
• Polygenic
HLA
-CH
LA-B
HLA
-A
DR
DQDP
Possible MHC class I combinations in one individual: 2A + 2B + 2C = 6
MHC FunctionHow 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
-CH
LA-B
HLA
-A
DR
DQDP
240470 110220 350451989
Possible MHC class I combinations in the human population: 470 x 110 x 240 = 1,240,800
MHC FunctionHow 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 FunctionHow 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
HLA
-CH
LA-B
HLA
-A
DR
DQDP
240470 110220 350451989
>2,000 peptides per class I molecule >> 2,000 peptides per class II molecule~105 molecules per cell
