Major Histocompatibility

Complex (MHC)
Lecture 8
Wesam Mohammed Emharib
Introduction
 MHC genes are genetic loci comprise of set of associated genes encoding many proteins
involved in antigen presentation.
 MHC glycoproteins were first acknowledged by their powerful immune response to
transplanted tissue. And these first two points explain origin of MHC term
 T cell receptor recognize particular pathogen as foreign peptide bound to MHC
 T cells organized into two main groups which differ in type of certain cell surface
protein. T helper express CD4 and T cytotoxic express CD8 and each of them recognize
different class of MHC. CD4 recognize antigenic peptide presented on MHC II whereas
CD8 recognize antigenic peptide presented on MHC I
 There is difference in antigen recognition between B and T cells. B cells and antibodies
can recognize intact antigen (Protein ) whereas T cell recognize specific amino acid
sequence which may hidden within protein folds, thus T cell unable to recognize this
sequence unless antigen (protein ) processed into peptides fragments.
 Antigen processing mean modification of intact antigen, whereas antigen presentation
mean displaying peptide sequence of antigen on cell surface by MHC
 The main body of this lecture:
1) MHC expression
2) MHC structure
3) Antigen processing and presentation
4) MHC polymorphism

 MHC expression
 MHC I present peptide form obligate intracellular pathogen (commonly viruses).
Because of the viruses can infected any nucleated cells, almost all nucleated cells
express MHC I
 Level of MHC I expression differ through nucleated cells for example; cells of
immune system express high level of MHCI whereas hepatocyte express low level of
MHC I in other hand the red blood cell express little or no MHCI
 Level of expression on RBC explains two clinical phenomena. Firstly no expression of
MHC I on RBC not clinically important in pathogenesis of viral infection because RBC
cannot support viral replication. Secondly in some kind of other intracellular
infection e.g. plasmodium species the causative agent of malaria, the RBC represent
privileged site to this infection due absence of MHC I.

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  In contrast, MHC II expressed on antigen presenting cells (macrophage, dendritic
and B cells) but not in other tissue cells.
 Expression level of MHC I and MHC II regulated by cytokines especially “ interferon “

 MHC structure
 Structurally, MHC class I and II are close to each other despite some differences in
their subunit structure
 MHC I consist of two polypeptide chains long α and short β, α polypeptide chain
encoded by MHC genetic locus whereas β polypeptide chain is not encoded by MHC
genetic locus
 Long polypeptide chain ( α) extents through the membrane
 In general MHC I formed of four domains, three domains form α chain and one
domain form β chain
 Peptide binding site (site of peptide presentation) formed of α1 and α2 domains. It is
also highly polymorphic site.

Figure 1: schematic shows structure of MHC I

 MHC II consist of two equal α and β polypeptide chains and both of them cross the
membrane
 Both α and β polypeptide chain encoded by genes in MHC locus
 In general MHC II consists of four domains, two domains form α chain and two
domains form β chain.
 The polymorphic Peptide binding site is formed of α1 and β1 domains

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 Figure 2: schematic shows structure of MHC II

 Antigen processing and presentation

 Type of infection determines type of immune response. In other words; the cytosolic
pathogen presented on MHC I to T cytotoxic cell whereas the intra-vesicular
(endocytic vesicle ) pathogen and extracellular pathogen presented on MHC II to T
helper cells

Cytosolic pathogen Intra-vesicular Extracellular

pathogen pathogen and
toxins
Digested into In cytoplasm In engulfed vesicle In engulfed vesicle
peptides
Peptides presented MHC I MHC II MHC II
on
Peptides presented CD8 (T cytotoxic ) CD4 (T helper 1) CD4 (T helper 2 )
to
The immunological Apoptosis Killing of intra B cell activation to
effect on presenting vesicular pathogen produce antibodies
cell to eliminate the
extracellular
pathogen

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Firstly / processing and presentation of antigens linked to MHC I

 Peptide binding site of MHC I is formed in lumen of endoplasmic reticulum

 Proteins are degraded into peptides in cytosol by multi-catalytic –protease –complex
called proteasome.
 Proteasome processing proteins of cells which continually replaced by new proteins
 Peptides transported into lumen of endoplasmic reticulum
 Peptides which are long can be terminated in endoplasmic reticulum by enzyme
called ERAAP (Endoplasmic Reticulum Aminopeptidase associated with Antigen
Processing)
 Transportation of peptides from cytosol to lumen of endoplasmic reticulum is aided
by TAP proteins (Transporters associated with Antigen Processing). TAP1 and TAP 2
form channel through which peptide pass from cytoplasm to lumen of endoplasmic
reticulum.
 TAP proteins encoded by genes in MHC locus and their expression induced by
interferon
 Recent experimental studies demonstrate that mutation in genes encode TAP
proteins block antigen presentation by MHC I
 Newly synthesized MHC I α chain inter endoplasmic reticulum and cannot leave it
until they bind to peptides. The retention of MHC I is aided by chaperon protein
called Calnexin, when α and β chains bind to each other, Calnexin dissociated from
MHC I
 Another protein have the same chaperon function of Calnexin will bind to MHC I this
protein called Calreticulin
 Second protein will added to this complex called Tapasin which linke btween MHC I
and TAP proteins thus allowing MHC I to wait suitable peptides from cytosol.
 Final component of this complex protein called Erp 57 which act on formation
disulfide bound between peptides and MHC I
 “ Peptide loaded MHC I ” is released from proteins complex and exported to cell
surface

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 Figure 3: processing and presentation of cytosolic proteins

 Some viruses evade the immune response by preventing appearance of peptides on

MHC I thus can stay safe and away from CD8 T cell for example:
1) Herpes simplex virus prevent transport of viral peptides into endoplasmic
reticulum by producing protein that bind and inhibit TAP
2) Adenovirus produce protein binds to MHC I to retain it in endoplasmic reticulum
3) Cytomegalovirus translocate MHC I from endoplasmic reticulum to cytosol where
they are degrade.

Secondly/ processing and presentation of antigens linked to MHC II

 In this case degradation of antigenic proteins occurs in endosome.

 PH of endosome decline to become acidic PH which activate protease exist in
endosome vesicle to digest antigenic proteins into peptides
 At the same time the vesicles contain newly synthesized MHC II during their passage
to cell surface combining with acidic vesicle. As result of this fusing MHC II will bind
to antigenic peptide and transport it to cell surface.

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 Like other surface proteins Synthesis or assembly of MHC II occur in endoplasmic
reticulum. Thus it must be prevented from binding to peptides in endoplasmic
reticulum during their biosynthesis
 Binding of peptides to MHC II in endoplasmic reticulum is prevented by protein
called MHC II associated invariant chain (li)
 MHC II associated invariant chain (li) degraded in acidic vesicles leaving short part
called CLIP ( class II associated invariant chain peptide ) which bind to peptide
binding site
 Another protein called class II like molecule (HLA-DM) catalyzing release of CLIP
and binding of peptide to MHC II
 Finally MHC II peptide complex travel to cell surface.

Figure 4: processing and presentation of intra-vesicle antigen

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Figure 5: intra-vesicular antigen processing and presentation

 MHC polymorphism
 There is many allelic form of MHC which differ from each other by amino acid
substitution in peptide binding site and regions that contact with T cell receptor
 Thus ; Polymorphism increases extent of antigens which immune system can
recognize
 Other benefit of MHC polymorphism that individuals in population will vary in MHC
molecules that they express and will therefore present different sets peptides from
each pathogen, thus make the susceptibility to given pathogen among population
unequal and its spread there for is limited
 Also increase variety of expressed MHC molecules decrease probability that
pathogen will be capable to prevent presentation and entirely evade immune
response.
 Reorganization of particular antigenic peptide presented on particular allelic variant
of MHC called ( MHC restriction )
 Reference : Janeway et al 6ed.2005. Immunobilogy . Garland science