UNIT -4 CSIR NET

Major Histocompatibility Complex

“Change is not merely necessary for

life. It is life.”

• A Toffler
MHC-structure

Major Histocompatibility Complex (MHC):

linked cluster of genes, which products play a role in
intercellular recognition between self and nonself.

The MHC is a region of multiple loci that play

major roles in determining, whether transplanted
tissue is accepted as self (histocompatible)
or rejected as foreign (histoincompatible)
 The concept of Histocompatibility

A skin-graft transplanted from A donor to a genetically identical

recipient is accepted, to a genetically disparate recipient is
 Nomenclature

• MHC = Major Histocombitibiliy Complex

• Minor Histocompatibility Antigens: proteins, which
are cell surface expressed and their peptides are loaded
into MHC molecules
• MHC is a generic name
• HLA = Human Leucocyte Antigen, eg SLA = Swine
Leucocyte Antigen
• Mouse: MHC has an historical name = H2 (H-2)
stands for histocompatibility 2
 Table of contents

• Introduction
• Structure of MHC I and II molecules
• Genetic organisation of the MHC
• Polymorphisms of MHC alleles
• MHC and disease
• Quiz
 Communication of cells in the body
1.) Cell cell contact via cell surface receptors:
cell surface proteins have been classified as CDs
(=cluster of differentiation)
CD2
T cell DC
TCR MHC
CD28 B7

2.) Cell to cell contact via soluble mediators such as

cytokines (interleukins-IL) or chemokines (CCR, CXCR)
IFN-g
T cell DC
TCR MHC
CD28 B7

IL-12
 Host defense

Against intracellular infection by Against

viruses intracellular infection by mycobacteria
MHC class I molecules present antigen derived from
proteins in the cytosol
MHC class II molecules present antigen originating
in intracellular vesicles
MHC molecules on the cell surface display peptide
fragments
 MHC

• Cluster of genes that influence:

1. Intercellular recognition
2. Self vs. non-self

• HLA complex in humans

 HLA Complex
• Three regions
• Class I genes
• MHC I molecules
• Nucleated cells
• T cytotoxic cells (CD8)
• Class II genes
• MHC II molecules
• APCs
• T helper cells (CD4)
• Class III genes
• Complement components (C2 and C4) plus TNF
 MHC I Molecules
• Membrane bound glycoprotein (Ig super family)
• Alpha chain
• Three domains
• Encoded by HLA complex
• Anchored in cell membrane
• Cytoplasmic tail
• Beta chain
• A single domain
• Encoded by a different gene on another chromosome
• Not anchored in cell membrane
• Bound to alpha chain non covalently
• Necessary for MHC I expression
 MHC I Molecules

• Antigen presenting features

• Alpha 1 and alpha 2 domains form peptide-binding cleft
• 8-10 amino acid peptides can bind to MHC I molecule
• Alpha 3 interacts with CD 8 on T cytotoxic cells
 MHC II Molecules
• Membrane bound glycoprotein (Ig super family)
• Alpha chain
• Two domains
• Encoded by HLA complex
• Anchored in cell membrane
• Cytoplasmic tail
• Beta chain
• Two domains
• Encoded by HLA complex
• Anchored in cell membrane
• Cytoplasmic tail
 MHC II Molecules

• Antigen presenting features

• Alpha 1 and beta 1 domains form peptide-binding pocket
• 13-18 amino acid peptides can bind to MHC II molecule
• Alpha 2 and beta 2 interact with CD 4 on T helper cells
Fig 7-5
 MHC I – Peptide Interaction
• Stable associations
• Endogenously processed antigens
• Up to six allelic variants
• ~100,000 MHC molecule variants per cell
• ~ 100 MHC-peptide complexes required for T cytotoxic cell
recognition
 MHC II – Peptide Interaction
• Stable associations
• Exogenously processed antigens
• Up to 12 allelic variants
 MHC Diversity
• Genetically determined
• Polygenic characteristic
• Different alleles
• Genes with overlapping functions

• ~12 million haplotypes

• Diversity in HLA type
 MHC I Expression
• Varies by cell type
• Lymphocytes high
• Hepatocytes low
• Regulated by cytokines
• Interferons
• TNF
• Suppressed by viruses
• Herpes family
• Hepatitis B
Inheritance of MHC(HLA) Type
• Polymorhisms
• Many allelic types within a species
• Haplotype
• The genetic loci of MHC are closely linked
• Inherited as a group (haplotype)
• One haplotype from each parent
• Co-dominant expression
 Inheritance of MHC
• Inbred mice
• Homozygous parents
• F 1 generation has MHC loci from both (heterozygous)
• F1 generation can accept grafts from either parent
• Neither parent can accept graft from F1 offspring
• WHY?
 Inheritance of MHC
• Humans
• Heterozygous parents
• F 1 generation has MHC loci from both (heterozygous)
• Four combinations
• F1 generation can not accept grafts from either parent
• Neither parent can accept graft from F1 offspring
• 1 in 4 F1 generation are HLA compatible
Antigen Processing &
Presentation
Content Outline
• Self MHC Restriction of T Cells
• Role of Antigen Presenting Cells
• Two Presentation Pathways
• Cytosolic Pathway: Endogenous Antigens
• Endocytic Pathway: Exogenous Antigens
• Clinical Applications
MHC antigens codominate

53
Mixed Lymphocyte Reaction

38
Self MHC Restriction of T Cells
• CD4+ & CD8+ cells
• Antigen must be in cleft of MHC
• MHC polymorphism
• ~500 antigens/cleft
Haplotype Restricted Cytotoxicity

56
“Antigen Pulse”
• “Antigen pulsed” macrophages
• T helper (CD4+) cells can only be stimulated by macrophages with
the same MHC Class II
• Cytotoxic (CD8+) T cells can only be stimulated by macrophages with
the same MHC Class I
T Cell Activation
MHC I: Biological function

44
MHC II: Biological function

47
MHCII: Biologogical function (2)

46
MHCII: Function

50
Role of Antigen Presenting Cells
• Immunize with native protein
• Boost with native protein
• B cell & T cell response
• Boost with denatured antigen
• T cell response only
• 2 different mechanisms APC for cell mediated & humoral
Antigen Presenting Cells
• Professional APC
• Dendritic cells
• Macrophages
• B Cells
• Non Professional APC
• Fibroblasts
• Glial cells
• Thymic epithelial cells
• Vascular endothelial cells
Dendritic cells
• Lot MHC-II
• co-stimulate
• activate T helpers
Macrophages
• Engulf microbe first
• digest antigen
• bind to MHC-II
• co express with B7 membrane protein
B Cells
• Constitutively express MHC-II
• activated
• then express B7
Two Presentation Pathways
• Cytosolic-
• MHC-I
• endogenous antigens
• Endocytic -
• MHC-II
• exogenous antigens
Cytosolic Pathway: Endogenous Antigens
• Ubiquitin & ATP
• Bind to peptide
• proteasomes
• Bind ubiquitin
• peptide transport
• Assembly of peptides in MHC-I
• Rough Endoplasmic reticulum
• Export to membrane
TAP proteins
• Transports associated with Antigen Processing
• TAP-1 TAP-2
• Transfer Peptides from proteosome to RER
TAP-1 TAP-2
Calnexin & MHC-1
Assembly in RER
• TAP-1 TAP-2 transport into ER
• Bind to Calnexin MHC-I
• Add peptide to MHC-I
• Release calnexin
• Transport to Gogli
Endogenous
Pathway
MHC-i
Endocytic Pathway: Exogenous Antigens
• endocytic vesicles
• peptide transport
• Assembly of peptides in MHC-II
Endocytic Route
• From Outside- phagocytosis
• From Inside
• Make MHC-II
• Bind Invariant chain
• CLIP- digests invariant chain
• Fuse
• MHC-II & clipped I & peptide
• peptide displaces clipped I chain
Invariant chain & MHC-II
Exogenous
Pathway
MHC-II
Key Terms
• antigen presenting cells[253],professional antigen presenting
cells[253],
• nonprofessional antigen presenting cells[253],cytosolic
pathway[255],,
• endocytic pathway[258], ubiquitin [255], proteosome[255],
• Transportors associated with antigen processing (TAP) [256],
• molecular chaperones[257], calnexin[ 257], invariant (Ii) chain [258],
• CLIP [259],
Key Concepts
• Describe self MHC restriction.
• Compare the cytosolic pathway for antigen presentation
with the endocytic pathway for antigen presentation
• Compare professional with non professional antigen
presenting cells.
• Draw a flow diagram comparing cytosolic and endocytic pathways for
processing antigens [Fig 10-4]
• Describe peptide generation by proteasomes.
• Describe transport of antigenic peptides from the cytosol to the
Rough Endoplasmic reticulum
• Draw a concept map for the separate antigen presenting pathways for
endogenous and exogenous antigens.
• Describe the assembly of MHC-II molecules within the rough
endoplasmic reticulum.
• Describe the development of a viral vaccine that uses the cytosolic
pathway.
Short Answer Questions
• Describe the development of a vaccine that used the
endocytic pathway.
• Name thee types of professional APCs.
• For each type indicate whether it expresses MHC-II
molecules and a co-stimulatory signal constitutively or
must be activated before doing so.
• Describe the role of ubiquitin in the processing of
endogenous antigens.
• Describe the role of calnexin in the assembly of MHC-I.
• T cells can react only with protein fragments.
• What is this process called?
• How does it occur?
• Which pathway leads to antigen interaction with MHC-I
molecules?
• Which pathway leads to interaction with MHC-II
molecules?
DONE!!!