Transcript Document

Major
Histocompatibility
Complex
Antigen
Presentation
APC to T-cell
MHC
• The immune system relies on many
regulatory mechanisms that govern
its ability to respond to infectious
agents and neoplastic tissues, but no
single scheme is as much a cellular
and molecular microcosm of
complex biologic systems as that
controlled by the Major
Histocompatibility Complex (Mhc).
MHC
• The Mhc is a set of linked genes,
located on chromosome 6 of the
human, chromosome 17 of the
mouse, and chromosome 20 of the
rat, that was first identified for its
effects on tumor or skin
transplantation and control of
immune responsiveness.
•
•
MHC
Although the control of transplantation,
autoimmunity, and the other immune
responses are the phenotypic
consequences of the function of
molecules encoded in the Mhc,
understanding the Mhc becomes clear if
we think of it in molecular and cellular
terms.
MHC molecules are cell surface receptors
that bind antigen fragments and display
them to various cells of the immune
system, most importantly T-cells that bear
ab receptors.
MHC
• The goal of this lecture will be to outline
the general principles of molecular
organization and function of both the
genetic regions that encode MHC
molecules and the functional cell
surface molecules themselves.
Major Histocompatibility Complex
• The major function of the
molecules encoded by the
MHC is to facilitate the
display of unique
molecular fragments on
the surface of cells in an
arrangement that permits
their recognition by
immune effectors such as
T-lymphocytes.
Major Histocompatibility Complex
• The MHC molecule
accomplishes its major role in
immune recognition by
satisfying two distinct
molecular functions: the
binding of peptides (or in
some cases nonpeptidic
molecules) and the interaction
with T cells, usually via the ab
T-cell receptor (TCR).
The binding of peptides by
an MHC-I or MHC-II
molecule is the selective
event that permits the cell
expressing the MHC
molecule (the antigenpresenting cell, APC) to
sample either its own
proteins (in the case of
MHC-I) or the proteins
ingested from the
immediate extracellular
environment (in the case of
MHC-II).
Major
Histocompatibility
Complex
•
In particular, cell
surface MHC class I
glycoproteins gather
from the cell’s
biosynthetic pathway
fragments of proteins
derived from infecting
viruses, intracellular
parasites, or self
molecules, either
normally expressed or
dysregulated by
tumorigenesis, and
then display these
molecular fragments at
the cell surface.
MHC I
Fig 4-4
MHC Class I
• The a chains forms a platform of 8stranded anti-parallel b pleated
sheet supporting two parallel
strands of a-helix.
• The formed cleft can bind peptides
of 8 -10 amino acids in a flexible
extended conformation.
MHC Class I
• The a3 segment
of the MHC I
serves as a binding
site for CD8.
• The b2microglobulin
interacts with the
a3 non-covalently.
MHC Class I
• The a chain the
HLA-A, -B, -C
MHC Class II
• Class II are composed of 2 noncovalent associated peptides, a chain
and b chain.
• The peptide binding cleft can
accommodate peptides up to 30 amino
acids in length.
MHC Class II
• The b2 is the
binding site for
the CD4.
• The a chains are
the HLA DR
• The b chains are
the HLA DQ and
DP
MHC Class II
MHC I
Peptides
derived from
proteins found
in the cytosol
that are then
degraded by
the
multiproteolytic
proteasome
complex into
peptides.
MHC I
The resulting
peptides, transported
from the cytosol to the
endoplasmic reticulum
with the aid of the
intrinsic membrane
transporter, the
transporter associated
with antigen
processing (TAP), are
then cooperatively
folded into the newly
synthesized MHC-I
molecule.
• The MHC-I molecule, the
ability to interact with
TCR, then allows the
APC bearing a particular
MHC–peptide complex to
engage an appropriate
ab TCR as the first step
in the activation of a
CD8+ cellular program
that might lead to
cytolysis of the APC as a
target and/or to the
secretion of lymphokines
by the T cell.
MHC I
MHC I Differential response
Potentially any nucleated cell
• MHC class II
molecules bind
peptides derived
from the
degradation of
proteins ingested by
MHC-II–expressing
APC, and display
them at the cell
surface for
recognition by
specific Tlymphocytes.
MHC II
MHC II
The MHC-II antigen
presentation
pathway is based
on the initial
assembly of the
MHC-II ab
heterodimer with a
dual function
molecule.
MHC II
The invariant
chain (Ii) that
serves as a
chaperone to direct
the ab heterodimer
to an endosomal,
acidic protein–
processing location.
MHC II
Where Ii encounters
antigenic peptides, it
serves to protect the
antigen-binding site of
the MHC-II molecule
so that it preferentially
will be loaded with
antigenic peptides in
this endosomal–
lysosomal location.
MHC II
The loading of the
MHC-II molecule with
antigenic peptide, a
process dependent on
the release of the Iiderived CLIP peptide,
in part dependent on
the MHC-II-like
molecule leads to the
cell surface expression
of MHC-II peptide
complexes.
MHC II
TH 1
TH 2
MHC I versus MHC II
• The MHC-I antigen presentation pathway is most
easily thought of as an inside-out pathway by
which protein fragments of molecules synthesized
by the cell are delivered to and bound by the MHCI molecule during its biosynthesis.
• In contrast, the MHC-II antigen presentation
pathway is best more clearly visualized as an
outside-in one in which ingested proteins are
degraded by enzymes in the endosomal–
lysosomal system and are delivered to the MHC-II
molecules in that degradative compartment.
MHC I versus MHC II
• The MHC-I and MHC-II molecules also
show preferential restriction to T cells of the
CD8- or CD4-bearing subsets.
• This is related to the observation that CD8
binds to the nonpolymorphic a3 domain of
MHC-I molecules, while CD4 interacts with
membrane proximal domains of MHC-II.
Viruses and MHC
• There is little question that the
immune system plays a decisive role
in host defense against microbial
pathogens, and it should not have
come as a surprise to find that many
pathogens have the ability to
produce molecules that modulate the
host response.
Viruses and MHC
The most striking results have been obtained for
viruses and MHC class I molecules.
• (a) peptide binding to TAP (ICP47 of
herpes simplex) or peptide translocation
by TAP (US6 of human cytomegalovirus);
• (b) stable insertion of the class I heavy
chain into the ER membrane (US2 and
US11 of human cytomegalovirus and HIV
vpu;
Viruses and MHC
The most striking results have been obtained for
viruses and MHC class I molecules.
• (c) release of assembled class I–peptide
complexes from the ER (E19 of
adenovirus);
• (d) inhibition of MHC class I heavy-chain
gene transcription (adenovirus, HIV); and
• (e) accelerated clearance of surface class I
(HIV Nef).
Viruses and MHC
The most striking results have been obtained for
viruses and MHC class II molecules.
• Epstein-Barr virus produces a molecule
that binds the human DR b chain.
• The T-cell response to herpes simplex in
humans has been found to have the
unusual feature of eliciting primarily CD4+
cytotoxic cells, and not stimulating much
in the way of a CD8+ CTL response.
•
Viruses and MHC
The most striking results have been obtained for
viruses and MHC class II molecules.
• Cells infected with herpes simplex were
found to have a defect in the stable
assembly of MHC class I heavy chain–b2m dimers and the export of class I
molecules to the cell surface, which later
was recognized to resemble the situation
in cells lacking effective peptide import
into the ER as a result of mutations in
TAP-1 or -2.
MHC I versus NK Cells
• The expression by the target cell of MHC
class I molecules can, in certain cases,
protect the target from killing by the NK
effector events, and target cells defective
in the expression of normal MHC class I
cells are susceptible to such NK-cell
lysis.
Human MHC Gene Chromosome 6
•
The genes encoding the chains of MHC
class I molecules and the a and b chains of
MHC class II molecules are linked within the
complex; the genes for b2-microglobulin and
the invariant chain lie on separate
chromosomes.
• Separate regions contain the genes
encoding the MHC class I and MHC class II
molecules, and within these regions there
are several genes for each chain.
Human Leukocyte Antigen
(HLA)
• In humans, there are three MHC Class I
a-chain genes, called:
HLA -A, -B, and -C.
• There are also three pairs of MHC
Class II a- and b-chain genes, called
HLA-DR, -DP, and -DQ.
HLA
• Tissue Type example:
• A1,28 B38,44 DR 4, 11
Autoimmunity
• The mechanisms of tissue damage in
autoimmune diseases are essentially the
same as those that operate in protective
immunity.
• Autoimmune responses are a natural
consequence of the open repertoires of
both B-cell and T-cell receptor that
allows them to recognize any pathogen.
Autoimmunity
• HLA genotype
• Diabetes Mellitus
DR3, DR4
• Juvenile Rhematoid Arth. B27
• Multiple Sclerosis
DR2
Mechanisms of Autoimmunity
• Another mechanism may by through
the binding of a superantigen
HLA vs. Transplantation
• HLA matching between the donor and recipient
- a predictor of graft survival in the kidney
allograft patient
• HLA mis-matches may cause chronic
pathologies in the allograft
• It is clear that a negative HLA-A2 recipient
receiving an allograft expressing HLA-A2 will
have a much higher risk of humoral rejection of
the vascular endothelium.
We love
learning about
MHC.
Monday we will
Have an exam