Download Antibody Structure and Function

The Major Histocompatibility
Complex And Antigen
Presentation
W. Robert Fleischmann, Ph.D.
Department of Urologic Surgery
University of Minnesota Medical School
[email protected]
(612) 626-5034
Objectives
• Learn the identity and biological roles of MHC
molecules.
• Learn the major classes and subclasses of
MHC molecules and their roles in immunity.
• Understand genetic polymorphism and its
significance for MHC molecules.
• Understand haplotypes and their significance.
• Learn the general structure of Class I and
Class II MHC molecules
• Learn how and where Class I and Class II
MHC molecules bind antigenic peptides.
What Are MHC Molecules?
• MHC = major histocompatibility antigens
– Aka the HLA (human leukocyte antigen)
complex in humans and the H-2 complex in
mice
• They were originally recognized for their
involvement in rejection of tissues
exchanged between two unrelated
organisms.
• Now, we know that MHC molecules play
an essential role in antigen recognition and
presentation to the immune system.
The MHC Region of the
Genome Is Large
• The MHC gene complex contains more than 100
separate loci (or genes) subdivided into Class I,
Class II, and Class III MHC molecules.
– Class I MHC molecules present antigen to CD8+
cytotoxic T cells.
– Class II MHC molecules present antigen to CD4+ helper
T cells.
– Other MHC proteins have been grouped together as
Class III MHC molecules. They include a diverse group
of proteins.
• Complement proteins
• TNF- and TNF-.
• Other loci encode enzymes, heat shock proteins, and some
molecules involved in antigen processing.
Importance of MHC Class I
and Class II Molecules
• B cells express B cell receptor that
recognizes antigen without the need for other
factors (specific antibody + Ig- and Ig-.
• T cells express T cell receptor (or, more
accurately, TCR + CD3) that recognizes
antigen only when the antigen has been
processed and presented to the T cell
receptor as an epitope bound to another
molecule. This other molecule is an MHC
molecule.
Three Major Classes of MHC
Molecules
• Class I MHC genes
– Present on nearly all nucleated cells
– Presents antigen to CD8+ cytotoxic T cells
• Class II MHC genes
– Present primarily on professional antigenpresenting cells (Ms, dendritic cells, B cells)
– Presents antigen to CD4+ helper T cells
• Class III MHC genes
– Complement proteins
– TNF- and TNF-
Note: Class I and Class II are structurally similar and bind and
present antigen. Class III molecules are very different
structurally and do not play a role in antigen presentation.
Class I MHC Have Subclasses
• Three “classical” Class I gene loci
– MHC Class I gene B encoding HLA-B
– MHC Class I gene C encoding HLA-C
– MHC Class I gene A encoding HLA-A
• There are a number of additional, non”classical” Class I gene loci
– The MHC gene locus D has since been identified
to constitute the Class II genes
– MHC Class I genes E, F, G, H
• Each of the Class I gene products associates
with another peptide, 2 microglobulin, when
they are expressed on the cell surface.
Class II MHC Have
Subclasses
• Each Class II MHC gene locus encodes
two peptides, an  subunit and a 
subunit that are expressed together on
the cell surface.
• Three major Class II gene loci
– MHC Class II gene DP encoding DP 
– MHC Class II gene DQ encoding DQ 
– MHC Class II gene DR encoding DR 
Each Major Class of MHC Has Subclasses
Kuby Immunology
Each Locus of Class I and Class II
MHC Is Highly Polymorphic
• There are many
alleles for each
classical Class I and
Class II locus.
• This polymorphism
– Gives us our unique
identity.
– Permits recognition of
self versus non-self.
– Is an impediment to
transplantation.
Medical Significance of MHC
Polymorphism
• This polymorphism
– Affects the ability to make an immune response.
– Affects the resistance or susceptibility to infectious
diseases.
• At least part of an individual’s ability to develop an immune
response is due to the individual’s MHC genes.
– Affects the susceptibility to autoimmune diseases and
allergies.
• HLA-B27 bearers are 90 times more likely to develop
ankylosing spondylitis (destruction of vertebral cartilage).
• HLA-DR2 bearers 130 times more likely to develop
narcolepsy.
• HLA-A3/B14 bearers are 90 times more likely to develop
hemochromatosis (too much iron absorption, deposited in and
damages internal organs).
Haplotypes
• Since Class I and Class II genes are closely linked,
recombination within the MHC region is rare.
• Thus, we inherit Class I and Class II loci from each of
our parents as a cassette of gene alleles.
– This cassette is called a haplotype.
– Our Class I and Class II make-up is composed of two
haplotypes, one maternal and one paternal.
– The alleles of each Class I and Class II locus are codominantly expressed in the same cells.
• For successful transplantation without
immunosuppression, a recipient would have to have
the same gene alleles within his/her two haplotypes
as the donor (syngeneic).
– Generally, only identical twins are syngeneic.
– Congenic, differ only in one locus.
A Single Cell Expresses MHC
Molecules That Represent the
Casette of MHC Molecules
Kuby
Note this example is for the mouse
MHC Class I Polymorphisms
• For MHC Class I
– 370 A alleles
– 660 B alleles
– 190 C alleles
• A total of 370 x 660 x 190 = 4.6 x 107 Class I
haplotypes for A, B, and C. (~2 x 1015 total)
• Class I E, F, G, and H are called Class Ib
proteins and are less polymorphic than A, B,
and C proteins. Class I E and G proteins bind
antigen peptides but are involved in NK cell
recognition.
• Most of the polymorphism differences are in the
cleft region (antigenic peptide binding site).
MHC Class II Polymorphisms
• For MHC Class II
– DR Locus
• 3 DR  alleles
• 400 DR 1 alleles
• ≥74 DR 2-9 alleles
– DQ Locus
• 28 DQ 1
• 62 DQ 1
– DP Locus
• ≥19 DP 1
• 118 DP 1
Stylized Structure of Class I
and Class II Molecules
Kuby
45 kDa  chain
12 kDa 2 microglobulin chain
33 kDa  chain
28 kDa  chain
Ribbon Diagrams of Class I & II
Molecules
Resident peptide
Roitt
Resident peptide
General Features of Peptide Binding
Clefts of Class I & II Molecules
• Similar structural features to peptide binding
clefts of both Class I & II
• There are up to 6 different Class I molecules
and up to 12 different Class II molecules
(mixing and matching of different  and 
subunits for a given set of alleles).
• Thus, binding of peptide to the peptide binding
clefts cannot be as strong as peptide binding to
antibody and T cell receptors.
Comparison of Binding Clefts
Class I Molecules
Class II Molecules
Nature of peptidebinding cleft
Closed at both ends
Open at both ends
General size of
bound peptides
8-10 amino acids
13-18 amino acids
Peptide motifs
Anchor residues at
involved in binding to both ends of peptide
MHC molecule
Anchor residues
distributed along the
length of the peptide
Nature of bound
peptide
Extended structure
that is held at a
constant elevation
above the floor of the
MHC cleft
Extended structure
with both ends
interacting and
middle arching away
from MHC cleft
Peptide Bound to MHC
Peptide-Binding Clefts
Kuby
Activation of T Cell by Antigenic
Peptide Bound to MHC
• Class I MHC presents antigen to CD8+ cytotoxic T
cells.
– If there are appropriate co-stimulatory signals and cytokines
produced, activation of the cytotoxic T cells may occur.
– Activation of cytotoxic T cells results in the death of cells
expressing the recognized antigen.
• Class II MHC presents antigen to CD4+ helper T
cells.
– If there are appropriate co-stimulatory signals and cytokines
produced, activation of the helper T cells may occur.
– Activation of helper T cells may result in the activation of B
cells to proliferate and differentiate into plasma cells.
– Activation of helper T cells may result in the activation of
CD8+ cytotoxic T cells to proliferate and attack antigen
bearing cells or in the ability of B cells to become antibodyproducing plasma cells.
T Cells Show Self-MHC
Restriction
• CD4+ and CD8+ T
cells from an
individual
recognize antigenic
peptides bound to
their own MHC
proteins.
• They do not
recognize antigenic
peptide bound to
allogenic MHC
proteins.
Syngeneic MHC
Cognate Antigen
Allogeneic MHC
Cognate Antigen
Syngeneic MHC
Non-cognate Antigen
Role of Antigen-Presenting Cells
• Processing of antigen is required for
recognition of an antigen by T cells.
• Most cells can present antigen with Class I
MHC.
– This includes the presentation of foreign antigen
and self-antigens.
– Recognition of antigen bound to Class I is by
CD8+ T cells.
• Professional antigen-presenting cell present
antigen with Class II MHC.
– Recognition of antigen bound to Class II is by
CD4+ T cells.
Professional AntigenPresenting Cells
• Dendritic cells are the most effective
– Constitutively express high levels of Class II MHC
molecules
– Constitutively express B7 and other costimulatory
molecules
• Macrophages
– Must be activated by phagocytosis to express Class II
molecules
– Must be activated to express costimulatory molecules
• B cells
– Constitutively express class II MHC molecules
– Must be activated by antigen binding to antibody
before they express costimulatory molecules
Different Antigen-Processing
and Presentation Pathways
for Different MHC Molecules
• Presentation of antigen on Class I
molecules requires intracellular protein
synthesis of the antigen.
• Presentation of antigen on Class II
molecules requires the endocytic uptake
of antigen.