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Major Histocompatibility
Complex (MHC) and T Cell
Receptors
Riandini Aisyah
March 2010

Principles of Immune Response

Highly specific recognition of foreign antigens
Mechanisms for elimination of microbes bearing
such antigens
A vast universe of distinct antigenic specifies
Immunologic memory
Tolerance of self-antigens

Major Histocompatibility Complex

(MHC)
Transfer of information about proteins within a
cell to the cell surface
MHC I are expressed on the great majority of
cells and recognized by CD8+ T cells
MHC II are expressed on B cells, macrophages,
dendritic cells and recognized by CD4+ T cells
Responsible for graft rejection
Found on chromosome 6 in human and 17 in
mouse
2003/11/26

System Biology

Historical Background
There were three kinds of molecules encoded by
the MHC
Class I
Class II
Class III

Class I MHC molecules are found on all

nucleated cells (not RBCs)
Class II MHC molecules are found on APC
Dendritic cells, Macrophages, B cells, other cells

Historical Background
Nucleated cells
Class I MHC
RBCs
Class II MHC
APCs

Figure 3-19

Figure 5-11

Structure of Class I MHC

Two polypeptide
chains, a long chain
and a short (2
microglobulin)
Four regions
Cytoplasmic region
containing sites for
phosporylation and
binding to cytoskeletal
elements
Transmembrane region
containing hydrophobic
amino acids

Structure of Class I MHC

Four regions
A highly conserved 3
domain to which CD8
binds
A highly polymorphic
peptide binding region
formed from the 1 and
2 domains

2-microglobulin helps
stabilize the
conformation

Structure of Class II MHC

Two polypeptide
chains, and , of
roughly equal length
Four regions
Cytoplasmic region
containing sites for
phosporylation and
binding to
cytoskeletal elements

Structure of Class II MHC

Four regions
Transmembrane region
containing hydrophobic
amino acids
A highly conserved 2
and a highly conserved
2 domains to which
CD4 binds
A highly polymorphic
peptide binding region
formed from the 1 and
1 domains

Figure 5-13

Figure 5-16

Important Aspects of MHC

Although there is a high degree of
polymorphism for a species, an individual has
maximum of six different class I MHC products
and only slightly more class II MHC products
(considering only the major loci).
Each MHC molecule has only one binding site.
The different peptides a given MHC molecule
can bind all bind to the same site, but only one
at a time.

Important Aspects of MHC

Because each MHC molecule can bind many
different peptides, binding is termed
degenerate.
MHC polymorphism is determined only in the
germline. There are no recombinational
mechanisms for generating diversity.
MHC molecules are membrane-bound;
recognition by T cells requires cell-cell contact.

Important Aspects of MHC

Alleles for MHC genes are co-dominant.
Each MHC gene product is expressed on the
cell surface of an individual nucleated cell.
A peptide must associate with a given MHC of
that individual, otherwise no immune response
can occur. That is one level of control.

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T cell activation

 Mature T cells must have a T cell receptor that

recognizes the peptide associated with MHC.
This is the second level of control.
Cytokines (especially interferon-) increase
level of expression of MHC.

 Peptides from the cytosol associate with class

I MHC and are recognized by Tc cells .
Peptides from within vesicles associate with
class II MHC and are recognized by Th cells.
Why so much polymorphism?

Survival of the species

Figure 5-2

Figure 5-7

Figure 5-7 part 1 of 2

Figure 5-7 part 2 of 2

Figure 5-10

One Receptors, Two Kinds of Signals

2003/11/26

System Biology

Peptides Binding to MHC Molecules

MHC I molecules bind short peptides, usually
between 8 and 10 residues.
The typical length of a class I ligand comprises 9
amino acids.
Class II ligands consist of 12 to 25 amino acids.
A core of nine amino acids is essential for
peptide/MHC binding.

2003/11/26

System Biology

MHC peptide prediction

Understanding the basis of immunity
Development of peptide vaccines
Immunotherapeutics for cancer and autoimmune
disease
Several mathematical approaches for MHC
peptide binding prediction

2003/11/26

System Biology

 Certain MHC molecule binds the corresponding

anchor residue of antigenic peptides.
Antigenic peptides which can combine with
the same kind of MHC molecule have same or simular
anchor sites and anchor residues
(consensus motif).

Comparison of anchor sites and anchor

residues in class I and II MHC molecules
NH2

C00H

Ag peptide

Anchor
residue

Anchor site

MHC-II
MHC-IImolecule
molecule

1.There are more anchor sites in class II MHC

molecules than that in class I MHC molecules.
2. Amino acid varieties of anchor residues in class II
molecules are more than that in class I MHC
molecules.

Structure of the T cell Receptor

Each T cell bears
TCRs of only one
specificity (allelic
exclusion)

Organization and Rearrangement of the T Cell

Receptor
Germline -Chain Gene
L

V1

V2

D1

L Vn

J11--------J16

C1

D2 J11---------------J17

C2
E

D-J rearrangement
L
P

V1

V2

L Vn

D1J15 C1

D2 J11---------------J17

C2

V-D rearrangement
L
P

LV2 D1J15 C1 D2 J11---------------J17

V1
P

C2
E

Transcription
V2 D1J15

C1
RNA

DNA

DNA

Comparison of TCR and BCR

Property

BCR (sIg)
Genes

TCR

Many VDJs, Few Cs

Yes

Yes

VDJ rearrangement

Yes

Yes

V regions generate Ag-binding site

Yes

Yes

Allelic exclusion

Yes

Yes

Somatic mutation

Yes

No

Transmembrane form

Yes

Yes

Secreted form

Yes

No

Isotypes with different functions

Yes

No

Proteins

Valence

Characteristics of interaction

1. Relative specificity
2. Flexibility

Biological functions of MHC

Participate in processing and presenting of

antigen
Participate in controling cell-cell recognition in
immunoreaction
Participate in genetic control for immune
response
Participate in inducing the differentiation and
development of T cell in thymus
Participate in inducing allograft rejection

I. Participate in processing and presenting of

antigen
Endogenous antigen:antigens synthesized
within cells
Exogenous antigen:antigens comes outside
the cell
Endogenous Ag is presented to CD8+ T cell
by MHC class I molecule
Exogenous Ag is presented to CD4+ T cell by
MHC class II molecule

CD8+T cell(Tc)

CD4+T cell(Th)

T cell
Receptor

T cell
Receptor

Peptide

CD4

MHC
Class II

Peptide

CD8

MHC
Class I

Antigen Presenting
Cell

Antigen Presenting
Cell

II. Participate in controling cell-cell recognition in

immunoreactionMHC restriction
In interaction of T cell and antigen-presenting
cell(APC) or target cell,T cell not only recognizes
specific antigen peptide,but also recognizes
polymophic residue of MHC molecules.That is to
say, interaction of T cell and antigen-presenting
cell(APC) or target cell need restriction by MHC
molecules. -----MHC restriction

 In interaction of Th cell and antigenpresenting cell(APC) is restricted by class II

molecules.
In interaction of Tc cell and antigenpresenting cell(APC) or target cell is restricted
by class I molecules.

Figure 5-17

Figure 5-18

Figure 5-19 part 1 of 2

Figure 5-20

III.Participate in genetic control for immune

response
IV.Participate in inducing the differentiation and
development of T cell in thymus
V.Participate in inducing allograft rejection

Key Steps in T cell Activation

APC must process and present peptides to T cells
T cells must receive a costimulatory signal
Usually from CD28/B7

Accessory adhesion molecules help to stabilize binding

of T cell and APC
CD4/MHC-class II or CD8/MHC class I
LFA-1/ICAM-1
CD2/LFA-3

Signal from cell surface is transmitted to nucleus

Second messengers

Cytokines produced to help drive cell division

IL-2 and others

MHC-Linked Diseases
Defects in MHC gene expression lead to
immunodeficiencies (MHC molecules are
required for both T cell development and
activation)
Some MHC alleles are associated with
susceptibility or resistance to autoimmune
diseases

MHC-Linked Immunodeficiencies
Bare Lymphocyte Syndromes lead to loss of MHC
molecule expression:
Defects in TAP genes prevent MHC Class I protein
surface expression (even though MHC proteins are
normal), so no CD8+ T cells - surprisingly mild
immunodeficiency (respiratory and skin infections)
Defects in TFs controlling Class II gene expression
(CIITA, RFXANK, RFX5, RFXAP) block CD4+ T cell
development - result in SCID (severe combined
immunodeficiency)

Fig. 13.20 Associations of HLA serotype and sex with susceptibility to

autoimmune disease.

1940s : Graft rejection

Transplantation antigen(histocompability antigen):
Antigens which cause immune response to the graft
and determine the survival of the graft.They are
alloantigen which is specific for each individual .
MHS(Major histocompatibility antigen system )
A group of complex histocompatibility antigens which
cause rapid and strong immunoreaction to the graft .

mHS(Minor histocompatibility antigen system)

A group of complex histocompatibility antigens
which cause slow and weak immunoreaction to
the graft .
MHC (Major histocompatibility complex)
A large cluster of linked genes located in some
chromosome of human or other mammals encode
for MHS and relate to allograft rejection, immune
response, immune regulation and cell-cell
recognition.

HLA (human leucocyte antigen)

The MHS of human which is associated with
allograft rejection, immune response, immune
regulation and cell-cell recognition.
HLA complex
The MHC of human,a cluster of the genes which
encode for HLA and relate to allograft rejection
immune response ,immune regulation and cell-cell
recognition.

Distribution of HLA molecules

1.class I HLA molecule
Expressed on all nucleate cells.
2.class II HLA molecule
Expressed on professional antigen-presenting
cell(macrophage,dentritic cell and B cell), activated T
cell, thymus epithelial cell et al.

Application of HLA in medicine

HLA and transplantation

Altered expression of HLA and disease
Some diseases are associated with HLA
genotypes
HLA and forensic medicine

What you should know by the end of this

lecture

Definition of MHC,HLA,HLA complex,anchor

residue
Composition of classical class I , II HLA genes and
antigen-pocessing and presenting associated
genes
Molecular structure and distribution of class I and
II HLA molecules
Biological functions of MHC molecules

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