Al-Anbar University / College of Medicine Assist Proff/ Noor N.
AL-Hayani
Dept. of Microbiology – Immunology
Major Histocompatibility Complex
(MHC)
The Major Histocompatibility Complex (MHC) is a set of molecules displayed on
cell surfaces that are responsible for lymphocyte recognition and antigen presentation. It is
control the immune response through recognition of "self" and "non- self", consequently
serve as targets in transplantation rejection.
There are three classes of MHC, class I, class II and class III MHC. The class I and class
II molecules belong to a group known as the immunoglobulin supergene family, which
includes immunoglobulins, T- cell receptors CD4, CD8 and others. In humans MHC
resides on the short arm of chromosome 6, three genes HLA- A, HLA- B and HLA- C code
for the class I MHC proteins while HLA- D determine the class II MHC proteins. MHC
can bind numerous different peptides and some peptides can bind to several different MHC
molecules and because this broad specificity, the binding between a peptide and an MHC is
often referred to as "promiscuous".
The locus of MHC class III contains genes encoding tumor necrosis factor, lymphotoxin
and complement components (C2 & C4). Class III MHC antigen not participate in MHC
restriction or graft rejection.
MHC class I
Class I MHC antigens are classical (HLA- A, HLA- B and HLA- C) and non classical
(HLA- E, HLA- F, HLA- G and HLA- X). These are glycoproteins found on surfaces of all
nucleotide human cells, fibroblast, muscle cell, liver hepatocyte, neural cells, this
contribute to the considerable success of liver transplantation. Class I antigens are involved
of MHC restriction of cell mediated cytotoxicity (Tc).
MHC class I structure & function: Class I molecules are composed of two
polypeptide chains, one encoded by the BCA region and another (β2 – microglobulin) that
is encoded elsewhere. The MHC encoded polypeptide is about 350 amino acids long and
glycosylated with molecular weight of about 45 kDa. This polypeptide folds into three
separate domains called alpha -1, alpha -2 and alpha -3. β2 – microglobulin polypeptide is
non – covalently associated with the alpha -3 domain. Between the alpha -1 and alpha -2
domains lies a region bounded by a beta-pleated sheet on the bottom and two alpha helices
on the sides. This region is capable of binding via non covalent interactions a small peptide
of about 10 amino acids and this small peptide is presented to a T- cell and defines the
antigen epitope that the T- cell recognizes.
Class I MHC molecules bind peptides and present them to CD8 T cells. These peptides are
derived from endogenous intracellular proteins that are digested in the cytosol. Then
transported from cytosol into the cisternae of the cytoplasmic reticulum, where they
interact with class I MHC molecules … this process known as the cytosolic or endogenous
processing pathway.
MHC class II
Class II MHC antigens are classical (HLA- DP, HLA- DQ and HLA- DR) and non
classical (HLA- DM and HLA- DO). HLA- DM facilitates the loading of antigenic
peptides into the class II MHC, DO serve as regulator of class II antigen processing. So,
these antigens are glycoproteins found on the surface of macrophages, B- cells, Dendritic
cells, Langerhans cells of skin and activated T cells. Class II antigens react with the CD4
molecule on the helper T- cells which secrete cytokines.
MHC class I structure & function: class II molecules are composed of two
polypeptide chains, both encoded by D region. These polypeptides (alpha and beta) are
about 230 and 240 amino acids long respectively and are glycosylated giving molecular
weights of about 33 kDa and 28 kDa. These polypeptides fold into two separate domains;
alpha- 1 and alpha -2 for the alpha poly peptide and beta -1 and beta -2 for the beta
polypeptide. The open groove of class II molecules accommodates slightly longer peptides
of 13-18 amino acids.
Class II MHC molecules bind peptides and present these peptides to the CD4 T cells
leading to secretion cytokines, like class I molecules it can bind a variety of peptides these
peptides are derived from exogenous proteins (either self or non self) which are degraded
with in the endocytic processing pathway.
"Diagram show function of MHC class I and class II "
T and B- Lymphocytes
B- cell maturation, activation and differentiation:
An immature B cell bearing IgM in its membrane leaves the bone marrow and matures
to express both membrane bound IgM and IgD with a single antigenic specificity. These
called naïve B cells which have not encountered antigen, circulate in the blood and lymph
and are carried to the secondary lymphoid organs, most notably the spleen and lymph
nodes. The generation of mature B- cells first occurs during embryonic stages and
continues throughout life. Before birth, yolk sac, fetal liver and fetal bone marrow is the
major sites of B- cell maturation; after birth maturation take place in the bone marrow. B-
cell development begins as lymphoid precursor cells differentiate into progenitor B cell
which proliferate and differentiate into precursor B cells, this maturation and
differentiation requires the microenvironment provided by the bone marrow stromal cells.
The IL-7 secreted by the stromal cells binds the IL-7 receptor on the pre-B cell and drive
the maturation process.
After export of B – cells from the bone marrow, activation, proliferation and differentiation
occur in the periphery in response to antigen. Activation of B- cell occur in the presence of
antigen, and in their absence the naïve B- cell in the periphery have a short life span and
dying within a few weeks by apoptosis. Activation of B- cell by a thymus dependent
antigen involve sequences events :
1. Antigen cross-link Igs receptors generating signal no.(1) which leads to increased
expression of class II MHC and costimulatory B7. Antigen – antibody complexes
are internalized by receptor – mediated endocytosis and degraded to peptides, some
of which are bound by class II MHC and presented on the membrane as peptide –
MHC complexes.
2. TH cell recognizes antigen – class II MHC on B cell membrane. This plus
costimulatory signal activates TH cell.
3. (1) TH cell begins to express CD40L.
(2) Interaction of CD40 and CD40L provides signal no.(2)
(3) B7-CD28 interactions provide costimulation to the TH cell.
4. (1) B- cell begins to express receptors for various cytokines.
(2) Binding of cytokines released from TH cell in a directed fashion sends signals
that support the progression of B- cell to DNA synthesis and to differentiation.
B- cell receptors:
The B- cell receptor (BCR) is a transmembrane protein complex composed of
membrane- bound immunoglobulin (mIg) and disulfide- linked heterodimers called Ig- α/
Ig- β . Molecules of this heterodimer associate with an mIg molecule to form a BCR. The
Ig- α chain has a long cytoplasmic tail containing 61 amino acids; the tail of Ig- β chain
contains 48 amino acids, the tails in both Ig- α and Ig- β long enough to interact with
intracellular signaling molecules.
In B- cell there are coreceptor provides simulatory modifying signals and another
membrane protein, CD22 provides inhibitory signals. The B- cell coreceptor is a complex
of three proteins: CD19, CD21 and CD81. CD19 is the key member of this complex and
has a long cytoplasmic tail that provides docking sites for molecules that augment signals
delivered by the BCR complex.
In addition to the stimulatory coreceptor, another molecule CD22 which is constitutively
associated with the B- cell receptor in resting B- cells, delivers a negative signal that makes
activation of B- cells more difficult.
Comparison of primary and secondary antibody responses:
Property primary response secondary response
Responding B cell Naïve B cell Memory cell
Time of peak response 7-10 days 3-5 days
Magnitude of peak antibody respons varies depend on Ag 100 – 1000 times higher
Isotype produced IgM predominates IgG predominates
Ag thymus dependent & thymus independent thymus dependent
Antibody affinity lower higher
T- cell maturation, activation and differentiation:
In most cases, both the maturation of progenitor T cells in thymus and the activation of
mature T- cells in the periphery are influenced by involvement of MHC molecules.
Progenitor T- cells begin to migrate to the thymus from the early sites of hematopoiesis in
the eighth or ninth week of gestation in humans. In the thymus, developing T- cells known
as thymocytes, proliferate and differentiate along developmental pathways that generate
functionally distinct subpopulations of mature T- cell.
The thymus occupies a central role in T- cell biology. Aside from being the main source of
all T- cells, it is where T- cells diversity and then shaped into an effective primary T- cell
repertoire by extraordinary pair of selection processes, so thymocytes undergo two
selection processes in the thymus:
Positive selection for thymocytes bearing receptors capable of binding self- MHC
molecules, which results in MHC restriction. Cells that fail positive selection are
eliminated within the thymus by apoptosis.
Negative selection that eliminates thymocytes bearing high- affinity receptors for
self- MHC molecules alone or self- antigen presented by self- MHC, which results
in self- tolerance.
The central event in the generation of humoral and cell- mediated immune response is the
activation and clonal expansion of T- cells. T- cell activation is initiated by interaction of
the TCR – CD3 complex with a processed antigenic peptide bound either a class I (CD8 +
cells) or class II (CD4 + cells) MHC molecule on the surface of an antigen presenting cell.
Interaction of a T- cell with antigen initiates a cascade of biochemical events that induces
the resulting T- cell to enter the cell cycle, proliferating and differentiating into memory
and effector cells. Also, Naïve T- cells require more than one signal for activation and
subsequent proliferation into effector cells:
Signal 1, the initial signal, is generated by interaction of an antigenic peptide with
the TCR – CD3 complex.
Signal 2, costimulatory signal, it is provided primarily by interactions between
CD28 on the T- cell and members of the B7 family on the antigen – presenting cell.
These two activation signals trigger entry of the T- cell into the G1 phase of the cell cycle
at the same time induce transcription of the gene for IL-2 and IL-2 receptor (CD25) this
increased 100- fold in the activation, proliferation and differentiation naive of T- cell. T-
cell activation generating a clone of progeny cells, which differentiate into memory and
effector cell populations. The various effector cells carry out specialized functions such as
cytokine secretion and B- cell help (activated CD4+ TH cells) and cytotoxic killing activity
(CD8+ CTLs)
(( Interaction of B7 family members on APCs with CD28 delivers the costimulatory signal,
while engagement of the closely related CTLA-4 (CD152) molecule with B7 produces an inhibitory
signal and down regulates the activation of the T- cell ))
T- cell receptor:
T- cell receptor is differs from B- cell antigen binding receptor in important ways, it is
membrane bound and does not appear in soluble form as B- cell receptor. the antigen –
binding interaction of T- cell receptors is weaker than that of antibodies and requiring more
sensitive assays, finally most T- cell receptors are specific not for antigen alone but for
antigen combined with (MHC) this attribute, called self- MHC restriction.
T- cell receptor is associated on the membrane with a multicomponent signal transducing
complex CD3 whose function is similar to that of the Ig- α/ Ig- β complex of the B- cell
receptor.
The molecule responsible for T- cell specificity is a heterodimer composed of either α and
β or γ and δ chains. The α and β TCR like the antibody is characterized by high degree of
specificity and consider a signature molecule of the adaptive immune system, By contrast
to γ and δ TCR function in a manner more consistent with innate immunity. The domain
structure of αβ and γδ TCR heterodimers are strikingly similar to those of
immunoglobulins. They are classified as members of immunoglobulin superfamily. Each
chain in a TCR has two domains containing an interaction disulfide bound that spans 60 –
75 amino acids, the amino terminal domain in both chains exhibits marked sequence
variation but the sequences is conserved in each chain. Finally, each TCR chain contains a
short cytoplasmic tail of five to 12 amino acids at the carboxyl-terminal end.
Finally, T- cell can be subdivided into two populations according to their expression of
CD4 or CD8 membrane molecules. CD4 T- cells recognize antigen that combined with
class II MHC molecules and function largely as helper cells, whereas CD8 T- cells
recognize antigen that is combined with class I MHC molecules and function largely as
cytotoxic cells.
Superantigens
Superantigens are viral or bacterial proteins that bind simultaneously to the V β domain
of a T- cell receptor and to the α chain of a class II MHC molecule. Cross – linkage of a T-
cell receptor and class II MHC molecule by either type of superantigen produces an
activating signal that induces T- cell activation and proliferation. There are exogenous and
endogenous antigen, exogenous antigens are soluble secreted bacterial proteins, including
various exotoxins. Endogenous superantigens are membrane – embedded proteins
produced by certain viruses, these viral proteins called minor lymphocyte-simulating (Mls)
determinants.
Comparison of antigen recognition by T cells and B cells:
Characteristic B- cells T- cells
Interaction with antigen involve binary complex of Involves ternary complex of
membrane Ig and Ag T- cell receptor, Ag and MHC.
Binding of soluble antigen yes No
Involvement of MHC molecules None required required to processed Ag
Chemical nature of antigens protein, polysaccharide & lipid Mostly protein
Epitope properties Accessible, hydrophilic and Internal linear peptides and
containing sequential or non Ag bound to MHC molecules
-sequential a.a.
