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Introduction to Immunology. Jianzhu Chen Department of Biology Massachusetts Institute of Technology jchen@mit.edu. Principles of adaptive immunity TCR recognition Antigen presentation and processing Host defense against viruses. Innate. Adaptive. Cells Ag receptors

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slide1

Introduction to Immunology

Jianzhu Chen

Department of Biology

Massachusetts Institute of Technology

jchen@mit.edu

  • Principles of adaptive immunity
  • TCR recognition
  • Antigen presentation and processing
  • Host defense against viruses
slide2

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.

slide3

Principle of the Adaptive Immunity

What is fundamental challenge faced by the immune system?

Fact:

Strategy:

Solution:

slide5

V

V

V

V

a

V

Key molecules and cells of the adaptive immunity

3 molecules

3 cell types

4 cardinal features

Antigen-presenting cells (APC)

Dendritic cells (DC)

Macrophage

B cells

B cells

T cells

slide6

Antigen recognition

by BCR and TCR

slide7

TCR-peptide-MHC

(pMHC) interaction

slide8

MHC Structure

Wiley et al. 1987

peptide

slide9

TCR-pMHC interaction

Extensive contacts:

between TCR and peptide

between TCR and MHC

TCR molecules are evolved to bind to MHC

major histocompatibility complex mhc
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)

slide12

MHC Restriction

MHC type determine the ability of T cell response.

Zinkernagel & Doherty, 1975

mhc structure

a

MHC Structure

Similar to Ig and TCR, belongs to the Ig superfamily

slide15

MHC Structure

Class I

 + 2m (2 microglobulin)

Class II

 +  subunits

peptide

peptide

2

1

1

1

Model:

3

2m

2

2

Simplified:

Gene:

a3

Tm

L

a1

a2

C

C

Peptide-binding proteins

Peptide is part of the stable structure (heterotrimers)

slide16

MHC Structure

Class I

Class II

Peptide

binding

cleft

Peptide

binding

cleft

b2m

slide19

MHC Structure

Cell

MHC

Denature

Peptide

mass spectrometry

Peptide Sequence

slide25

MHC Nomenclature

Mouse

H2-K

-D

-L

H2-IA

-IE

Class I

Class II

HLA-A

-B

-C

HLA-DP

-DQ

-DR

  • Human
    • Human
    • Leukocyte
    • Antigen

Example: HLA-A2 (or A2), human MHC class I A molecule, allele 2

Haplotype: each set of alleles

  • H2-Kd (Kd)IAd
  • Balb/c  H-2dH2-Dd (Dd)IEd
    • H2-Ld (Ld)
slide26

MHC Function

DP

DQ

DR

HLA-C

HLA-B

HLA-A

2b

2a

3b

2a

3b

1a

How can a small number of MHC molecules present a large number of peptides for TCR recognition?

  • Polygenic

Possible MHC class I combinations in one individual:

2A + 2B + 2C = 6

slide27

MHC Function

DP

DQ

DR

HLA-C

HLA-B

HLA-A

2b

2a

3b

2a

3b

1a

89

19

45

20

350

2

470

110

240

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

Possible MHC class I combinations in the human population:

470 x 110 x 240 = 1,240,800

slide28

MHC Function

Differences in amino acids are concentrated in the peptide-binding groove.

Different MHC molecules bind to different set of peptides

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.
slide29

MHC Function

DP

DQ

DR

HLA-C

HLA-B

HLA-A

2b

2a

3b

2a

3b

1a

89

19

45

20

350

2

470

110

240

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