Introduction to Immunology

Introduction to ImmunologyJianzhu Chen

Department of BiologyMassachusetts Institute of Technology

[email protected]

• 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