Introduction to Major Histocompatibility Complex (MHC) from University of Portsmouth

Introduction to Major Histocompatibility Complex (MHC)

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Learning Objectives

On completion of this session you should be able to

1. Understand the structure and function of MHC molecules.
2. Comprehend the genetics of MHC and the concept of MHC
   restriction in T cell activation.

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MHC and Immunity

How is MHC related to immunity?

1. Antibodies can recognise antigen alone
2. T-cell receptors can only recognise antigen that has been
   processed and presented by Major Histocompatibility
   Complex (MHC)
3. Involves antigen processing and antigen presentation

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MHC Genes

1. The MHC is a complex of genes located on the short arm of
   chromosome 6 in humans and chromosome 17 in mice
2. The MHC extends over 4-7 x 106 bp
3. The MHC comprises more than 200 genes divided into 4
   regions designated as Class I, Class Ib, II and III
4. The products of the MHC genes mediate:
   1. T cell development
   2. T cell recognition of antigen
   3. Rejection of tissue grafts
   4. Susceptibility to certain disorders

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Chromosome 6: HLA Region

Chromosome 6
Tel
Long arm
Cen
Short arm
Tel
HLA region
6p21.1-21.3
Class II
Class III
Class I
Bf
DP
DM
DQ
DR
C4 C2Hsp70TNF
B C
E AGF
+
Gene map of the human leukocyte antigen (HLA) region
Expert Reviews in Molecular Medicine@2003 Cambridge University Press

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MHC Protein Products

1. The most important products are the Class I and Class II
   proteins
2. The function of these proteins is to present peptide fragments
   to T cells
3. The MHC protein with bound peptide is the TCR ligand
4. CD8+ T cells bind to MHC Class I:peptide complexes
5. CD4+ T cells bind MHC Class II:peptide complexes

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Class I MHC Genes Function

1. Mediates immune responses against endogenous antigens,
   antigens that are already found in cells
2. Usually these cells that are expressing MHC class 1 are viral-
   infected or are tumour cells
3. MHC Class I presents peptides that are 8-10 amino acids in
   size, which will then be recognised by the cytotoxic T cells
4. Found in all nucleated cells

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Class II MHC Genes Function

1. Mediate immune response against exogenous antigens,
   antigens that are found outside of the cells, in the cytosol
2. Bind with amino acid residues that are 13-18 in size and will
   be recognised by T helper cells
3. MHC class II protein is found on cells like B lymphocytes,
   macrophages, monocytes, dendritic cells and endothelial cells
4. These cells are phagocytic and can engulf an extracellular
   antigen

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MHC Haplotypes

1. Set of genes located on a single chromosome and the
   characteristic dependent on them
2. An individual has 2 haplotypes of each set of genes
   (maternal/paternal)
3. MHC genes expressed codominantly (both maternal and
   paternal products) in same cells

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Class I MHC Proteins Structure

1. Comprise 2 polypeptide chains
   1. a chain (transmembrane)- encoded by MHC
   2. 2 macroglobulin (encoded by highly conserved gene on
      different chromosome)
2. Folded molecule
   has 4 domains:
   a1, a2 (create
   peptide binding
   cleft), a3, ß2
   peptide-binding
   cleft
   Q3
   ₿2-
   microglobulin
   d
   farland Science 2012)

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Class II MHC Proteins Structure

1. Comprise 2 polypeptide chains
   1. a chain
   2. 2. ß chain
2. Folded molecule has 4 domains: x 1, Qu'farland Science 2012)
   (transmembrane)
   peptide-binding
   cleft
   ₿1
   a1
   ₿2
   Q2
   d
3. a1 and 31 domains comprise peptide binding cleft

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MHC Proteins: Peptide Binding Cleft

1. Peptide Binding Cleft:
2. Similar organisation on class I and II proteins
3. Floor of cleft is ß sheet
4. Walls of cleft are & helices
5. Class I binding clefts are closed, class II are open
6. Peptides lie within the cleft in extended conformation

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Peptide Binding Clefts Visual

a
b
C
d
Figure 4.17 Janeway's Immunobiology, 8ed. ( Garland Science 2012)

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MHC Peptide Binding to Class I

1. Selective with high affinity to only certain peptides
2. Peptides are 8 - 9 residues long
3. Aliphatic/aromatic residues "anchor" peptide within the cleft
4. Anchor residues occur in all peptides binding a particular
   MHC class I molecule
   T-cell
   receptor
   Anchor residues
   Peptide
   (8-9 amino
   acid residues)
   Peptide-binding
   groove with allele-
   specific pockets
   MHC
   class I
   molecule

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MHC Peptide Binding to Class I Examples

HẸN+
3
R
GY
V
Y
Q Q
L
COO
HẸN*
3
S
N
F
E
K
L
HẸN
+
A
P
G
N
Y
P
A
L
COO
HÂN*
T
Y
Q
R
T
RA
L
V
COO
H2N+
S
Y
F
P
E
I
T
H
HẸN*
K
Y
Q
A
V
T
T
T
L
H2N+
S
Y
I PSA
E
K
I
COO
Figure 4.19 Janeway's Immunobiology, 8ed. (@ Garland Science 2012)

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MHC Peptide Binding to Class II

1. Bind peptides in variable length from 12 to about 17
   linearly arranged amino acids
2. Three (sometimes four) anchor residues in the
   central region of the peptide that bind to the
   allele-specific pockets of the MHC class II molecule
3. Class II proteins can bind greater range of peptides
   and anchor residues are more difficult to predict
   T-cell
   receptor
   Anchor residues
   Peptide
   (12-17 amino-acid
   residues)
   MHC
   class II
   molecule
   Peptide-binding
   groove with allele-
   specific pockets

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Self MHC Restriction

1. T cell can only recognise and respond antigenic peptide
   combining with MHC molecules
2. Helper T cells recognise antigen in context of class II self
   MHC
3. Cytotoxic T cells recognise antigen in context of class I self
   MHC

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Self MHC Restriction of Tc Cells

R. Zinkernagel & P. Doherty
LCM virus
H-2k
· Tc cells kill only
syngeneic virally
infected target
cells
. Both Tc cell and
infected cell
must share the
same set of
MHC genes
Spleen cells
(containing To cells)
51Cr
..
H-2k target cells
H-2k LCM-infected H-2bLCM-infected
target cells
target cells
1
-51Cr release
(no lysis)
+51Cr release
(lysis)
-51Cr release
(no lysis)

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Summary of MHC

1. Understanding the structure and function of MHC molecules is fundamental
   to immunology.
2. MHC class I molecules consist of a heavy alpha chain and a beta-2
   microglobulin chain, with a peptide-binding groove that presents endogenous
   antigens to CD8+ cytotoxic T cells.
3. MHC class II molecules, composed of alpha and beta chains, present
   exogenous antigens to CD4+ helper T cells, essential for coordinating
   immune responses.
4. MHC restriction, is the principle that T cells recognise antigens only when
   they are presented by the body's own MHC molecules. This ensures that T
   cells respond specifically to cells presenting foreign antigens in the context of
   self-MHC, thus maintaining immune precision and preventing inappropriate
   immune activation.

I KNIVEDOITV .-
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METTE

Antigen Processing and Presentation

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Learning Objectives for Antigen Processing

On completion of this session you should be able to

1. Comprehend the different pathways of antigen processing
   and presentation by MHC class I and II molecules.
2. Identify key molecular components involved.

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Antigen Processing and Presentation Overview

1. Antigen processing - the generation and binding of peptides to
   MHC molecules
2. Antigen presentation - displaying peptides on the cell surface
   in association with MHC molecules
3. MHC Class I and II molecules bind peptides derived from
   different cellular locations:
   Class I - cytosolic
   Class II - vesicular

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Antigen Processing and Presentation Pathways

Cytosolic pathogens
Intravesicular
pathogens
Extracellular
pathogens
and toxins
C
any cell
macrophage
B cell
Degraded in
Cytosol
Endocytic vesicles
(low pH)
Endocytic vesicles
(low pH)
Peptides bind to
MHC class I
MHC class II
MHC class II
Presented to
Effector CD8 T cells
Effector CD4 T cells
Effector CD4 T cells
Effect on
presenting cell
Cell death
Activation to kill
intravesicular bacteria
and parasites
Activation of B cells to
secrete Ig to eliminate
extracellular bacteria/toxins
Figure 6.2 Janeway's Immunobiology, 8ed. (@ Garland Science 2012)

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Antigen Processing and Presentation Machinery

Proteosome and TAP Transporter

The Processing "Machinery"

1. Proteosome -
   . Large, multicatalytic protease complex
   . ~ 28 subunits
   · Degrades cytosolic proteins
2. TAP Transporter - transporter associated with antigen
   processing
   •
   Heterodimer of TAP-1 and TAP-2 proteins (encoded by
   MHC)
   •
   Transports peptides across the endoplasmic reticulum
   (ER)

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Antigen Processing and Presentation Chaperones

Calnexin and PLC

1. Calnexin -
   ER membrane-bound protein (88 kDa)
   •
   · Retains MHC class I molecules in ER until peptide is
   bound
   . Chaperone protein
2. PLC (Peptide Loading Complex)
   · Comprises chaperone proteins:
   a
   calreticulin - similar function to calnexin
   b
   tapasin - links MHC Class I to TAP
   C
   ERp57 - mediates peptide binding to Class I

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Antigen Processing and Presentation Additional Components

ERAAP and Invariant Chain

1. Endoplasmic Reticulum Aminopeptidase associated with
   Antigen Processing (ERAAP)
   . Trims peptides to correct length
2. Invariant Chain (Ii, CD74) -
   · MHC Class II associated Invariant chain
   · Associates with newly formed MHC class II molecules to
   prevent peptide binding in ER
   . Targets delivery of new Class II molecules to low pH
   endosomes

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Antigen Processing and Presentation with Class I

Partly folded MHC class
I & chains bind to
calnexin until
B2-microglobulin binds
MHC class I a:B2m complex
is released from calnexin,
binds a complex of
chaperone proteins
(calreticulin, ERp57) and
binds to TAP via tapasin
Cytosolic proteins and
defective ribosomal
products (DRiPs) are
degraded to peptide
fragments by the
proteasome. TAP delivers
peptides to the ER
A peptide binds the MHC
class I molecule and
completes its folding. The
MHC class I molecule is
released from the TAP
complex and exported to
the cell membrane
MHC
class I
calreticulin
ERp57
ER
tapasin
₿2m
TAP
ERAAP
calnexin
normal proteins (>70%)
Cytosol
peptide
fragments
DRiPs
(<30%)
ribosome
proteasome
Nucleus
old protein
Figure 6.5 Janeway's Immunobiology, 8ed. (@ Garland Science 2012)

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Antigen Processing and Presentation with Class II

Invariant chain (li) forms
a complex with MHC
class II molecule,
blocking the binding
of peptides and
misfolded proteins
li is cleaved in an
acidified endosome,
leaving a short peptide
fragment, CLIP, still
bound to the
MHC class II molecule
Endocytosed antigens
are degraded to
peptides in endosomes,
but the CLIP peptide
blocks the binding of
peptides to MHC
class II molecules
HLA-DM binds to the
MHC class II molecule,
releasing CLIP and
allowing other peptides
to bind. The MHC class II
molecule then travels
to the cell surface
li
· HLA-
DM
Endoplasmic reticulum
Cytosol
Figure 6.12 Janeway's Immunobiology, 8ed. (@ Garland Science 2012)