Major histocompatibility complex (MHC)

Major histocompatibility complex

• The term ‘histo’ stands for tissue and ‘compatibility’ refers to ‘getting along or agreeable’. On the other hand, the term ‘complex’
refers to the ‘genes that are localized to a large genetic region containing multiple loci’.
• Major Histocompatibility complex is membrane-attached protein that work on intercellular recognition of antigens between
self and non-self body and antigen presentation
• Major Histocompatibility complex (MHC) is a set of surface proteins located on the cell membrane of nucleated cells.
• These genes code for antigens which are involved in the determination of the compatibility of the transplanted tissue.
• The immune system will accept the compatible tissues while the histo-incompatible ones are rejected.
• The rejection of foreign tissue leads to an immune response to cell surface molecules. The concept was first identified by Peter
Gorer and George Snell.
• The main function of MHC molecules is to bring antigens to the cell surface for recognition by T cells.
• MHC molecules always recognize only T lymphocytes. The two types of MHC work in immunity.
• T helper (Th) cell recognizes by MHC molecules II, and T cytotoxic (Tc) cells are recognized by MHC I molecules.
• In humans, the genes coding for MHC molecules are found in the short arm of chromosome 6.
• Histocompatible: transplanted tissue is successfully accepted as self
• Histocompatibility antigens: rejection of foreign tissue is the result of an immune
response to cell-surface molecules
• Histocompatibility complex : a region of multiple loci that play major roles in determining
whether transplanted tissue is with histocompatibility or histoincompatibility
• Major vs minor
• Major Histocompatibility Complex, MHC : rapid graft rejection –
• Minor Histocompatibility complex, mHC : slow graft rejection •
• HLA: human leukocyte antigen, MHC antigens in human •
• H-2: MHC antigen in mice
Major Histocompatibility Complex (MHC) genes are a group of genes that play a crucial role in the immune
system by presenting antigens to T cells.
Some of the key features of MHC genes include:

• Polymorphism: MHC genes have high levels of genetic diversity, with many different alleles (versions of a gene) present in a
population. This helps ensure that the immune system can recognize and respond to a wide variety of pathogens.
• Diversity: MHC genes encode a diverse range of molecules that can present antigen to T cells, allowing the immune system to
respond to a wide range of pathogens and antigens.
• Antigen presentation: MHC molecules present fragments of foreign antigens to T cells.
• Linkage disequilibrium: MHC genes are tightly linked on chromosome 6, meaning that alleles at different MHC loci tend to be
inherited together.
• Evolutionary pressure: MHC genes are subject to strong selection pressure from pathogens, which drive the evolution of new
alleles and increase the diversity of the MHC.
• Role in disease susceptibility: Variations in MHC genes can affect an individual's susceptibility to certain diseases, such as
autoimmune disorders and infectious diseases.
• Involvement in transplantation: MHC genes play a critical role in transplantation, as mismatches between the donor and
recipient MHC can lead to rejection of the transplant.
Genes of MHC Organized In 3 Classes

Class I MHC genes

Glycoproteins expressed on all nucleated cells
Major function to present processed Ags to Tc
Class II MHC genes
Glycoproteins expressed on MF, B-cells, DCs
Major function to present processed Ags to Th
Class III MHC genes
Products that include secreted proteins that have immune functions.
Ex. Complement system, inflammatory molecules
Genes of MHC Organized In 3 Classes

Types
In humans, the MHC molecules are divided into three types, Class I, Class II and Class III.

1. Class I MHC molecules are coded from three different locations called A, B and C and these molecules are expressed in all nucleated cells.
2. Class II MHC genes are located in the D region and there are several loci such as DR, DQ and DP and these molecules are expressed only in
antigen-presenting cells.
3. Class III MHC genes are coded in the region between Class I and Class II genes. Class III MHC genes codes for cytokines and complement
proteins which play an important role during the immune response.

• The HLA (Human Leukocyte Antigen) system is the most polymorphic and best-studied MHC system, and is the primary system used in
transplantation and disease association studies.
• The HLA system is used to describe MHC molecules in humans and is divided into several subtypes, such as
• HLA-A, HLA-B, and HLA-C for MHC Class I, and
• HLA-DR, HLA-DP, and HLA-DQ for MHC Class II.
• These subtypes can vary greatly between individuals, which is why matching MHC molecules between donor and recipient is so important in
transplantation.
Structure of MHC class I
• Two polypeptide chains
• Long α chain and short β
• Four regions
• Cytoplasmic- contains sites for phosphorylation and
binding to cytoskeleton
• Transmembrane- contains hydrophobic AAs
• Highly conserved α3 domain binds CD8
• Highly polymorphic peptide binding region formed
by α1 and α2
Structure of MHC class I
Ag-binding groove
• Groove composed of
• α helix on 2 opposite walls
• Eight β sheets
• Groove binds peptides 8-10 AA long
• Specific amino acids on peptide are required for
“anchor site” in the groove
• Many peptides can bind
• Interactions at N and C-terminus are critical
and “lock” peptide in grove
• Center of peptide bulges out for presentation
• Consideration in vaccine development
MHC 1 Pathways of Ag presentation
 Class II MHC molecules
• Class II MHC molecules are heterodimers and characterized by two
non covalently connected polypeptide chains. The chains are termed
as a heavy chain (α, 30kDa) and light chain (β, 26kDa).
• Similar to class I MHC molecules, class II MHC molecules are also
characterized by an extracellular amino terminal domain, a
transmembrane domain and an intracellular carboxy terminal tail.
• The class II MHC molecules are expressed on the surface of the
antigen-presenting cells such as B cells, dendritic cells, and
macrophages.
• The α chain is divided into two domains α1 and α2, while the β chain
is also divided into two groups β1 and β2.
• The β2 domain is responsible for the binding of T cell co-receptor
CD4.
• The α1 and β1 domain, on the other hand, involved in the formation
of the antigen binding sites. Peptides containing 13-20 amino acids
can bind at the antigen-binding site of class II MHC.
• The presence of disulfide bonds in α2, β1, and β2 domains are also
an important structural feature of the class II MHC molecules.
Groove binds peptides 13-25 AA long (some outside groove)
Four regions
• Cytoplasmic - contains sites for phosphorylation and binding to cytoskeleton
• Transmembrane- contains hydrophobic AAs
• Highly conserved α2 and β2 domains- binds CD4
• Highly polymorphic peptide binding region formed by α1 and β1
MHC II presentation pathways
Class III MHC molecules

There are several serum proteases which involve in compliment system

come under the group of class III MHC molecules.

Class III MHC molecules do not have any involvement in antigen

presentation.

The complement components such as as C2, C4A, and C4B, and factor B
are the most important compounds involve as class III MHC molecules.

Apart from these tumor necrosis factors α and β and some heat shock
proteins also come under this category.
Important aspects of MHC

• Individuals have a limited number of MHC alleles for each class

• High polymorphism in MHC for a species
• Alleles for MHC genes are co-dominant
• Each MHC gene product is expressed on surface of individual cell
• Each MHC has ONE peptide binding site
• But each MHC can bind many different peptides
• Only one at a time
• Peptide binding is “degenerate”
• MHC polymorphism is determined in germline
• NO recombination mechanisms for creating diversity in MHC
• Peptide must bind with individual’s MHC to induce immune response
Important
aspects of MHC
Peptide in vesicle
• How do peptides get into
MHC groove? Displaces Ii chain
golgi
• Class I: peptides in
cytosol associate with
MHC Ii chain
• Class II: peptides from Class I Class II
within vesicles
ER
associate with MHC
Important aspects of MHC

• MHC molecules are membrane-bound

• Recognition by Ts requires cell-cell contact
• Mature T cell must have TCR that recognizes particular MHC
• Cytokines (especially IFN-γ) increase expression of MHC
HLA
Thank you
T cell receptor (TCR)
• The TCR is a complex of transmembrane proteins that are unique to each T cell
and are responsible for recognizing antigens presented by MHC molecules on
antigen-presenting cells (APCs).
• The TCR is composed of two different protein chains, alpha and beta, or gamma
and delta, that are associated with each other to form the TCR complex.
• The TCR has a highly diverse and combinatorial repertoire, which allows T cells to
recognize a wide range of antigens. The specificity of the TCR for antigen
recognition is determined by the complementarity-determining regions (CDRs) of
the TCR, which interact with the antigen presented by MHC molecules on
antigen-presenting cells (APCs).
• When a T cell encounters an APC presenting an antigen that matches the TCR,
this interaction can activate the T cell and initiate an immune response. The
specificity of the TCR for antigen recognition is crucial for the proper functioning
of the immune system, as it ensures that T cells only respond to antigens that
pose a threat to the body.
Important aspects of TCR
• Each T cell has TCR of only ONE specificity
• Each T cell has a unique T cell receptor (TCR) with a single specificity for a particular antigen. This is due to a
process called allelic exclusion, which occurs during T cell development in the thymus. Allelic exclusion
ensures that each T cell expresses only one functional TCR on its surface, allowing for the proper recognition
and response to antigens.
• αβ TCR recognizes Ag only in the context of cell-cell interaction and in correct MHC context
• γδ TCR recognizes Ag in MHC-independent manner
• Response to certain viral and bacterial Ag
• During T cell development, the TCR genes undergo recombination to generate a diverse repertoire of TCRs.
However, as the T cell matures, only one TCR gene is expressed, while the other TCR genes are silenced. This
ensures that each T cell has a unique TCR with a single specificity for a particular antigen, allowing the T cell
to specifically recognize and respond to that antigen.
• Allelic exclusion is a crucial process in the functioning of the immune system, as it ensures that T cells are
able to recognize a wide range of antigens and respond appropriately to different threats.
 Role of TCR in immune response
• Surface molecule on T cells
• Recognize Ag presented in MHC context
• Two types of TCR
• α β: predominant in lymphoid tissues
• γ δ: enriched at mucosal surfaces
• Heterodimer
• α and β chains, approx. equal length
• Regions
• Short cytoplasmic tail- cannot transduce activation
signal
• Transmembrane with hydrophobic AAs
• Both α and β have a variable (V) and constant (C)
region
• V region is hypervariable, determines Ag specificity
Genetic basis for receptor generation
• Accomplished by recombination of V, D and J gene segments
• TCR β chain genes have V, D, and J
• TCR α chain genes have V and J
TCR and CD3 complex
• TCR is closely associated with CD3 complex
• Group of 5 proteins
• Commonly called “invariant” chains of TCR
• Role of CD3 complex
• CD3 necessary for cell surface expression of TCR
• transduces signal after Ag interaction with TCR
Key steps in T cell activation
• APC must process and present peptides to T cells
• T cells must receive co-stimulatory signal
• Accessory adhesion molecules stabilize binding of TCR and MHC
• Signal from cell surface is transmitted to nucleus
• Cytokines produced help drive cell proliferation
 The “immunological synapse”
• TCR-MHC interaction is not strong
• Accessory molecules stabilize interaction
• CD4/MHC class II or CD8/MHC class I
• CD2/LFA-3: The interaction between CD2 on T cells and LFA-3 (Lymphocyte
Function-associated Antigen 3) on APCs is important for the activation and
proliferation of T cells.
• LFA-1/ICAM-1- The interaction between LFA-1 (Lymphocyte Function-associated
Antigen 1) on T cells and ICAM-1 (Intercellular Adhesion Molecule 1) on APCs is
critical for the adhesion and migration of T cells during an immune response.
• Specificity for Ag is solely in TCR
• Cytokines change expression levels
• For example, cytokines such as interleukin-2 (IL-2) can upregulate the expression of
co-stimulatory molecules, such as CD28 and CD137, on T cells, enhancing T cell
activation and proliferation. Conversely, cytokines such as interferon-gamma (IFN-γ)
can downregulate the expression of adhesion molecules, such as LFA-1, on immune
cells, reducing their ability to adhere to other cells and tissues.
• Co-stimulation is also necessary for activation of T cells
• CD28/CD80 or CD86-CD28 is a co-stimulatory receptor expressed on T cells, while CD80 (also known as
B7-1) and CD86 (also known as B7-2) are co-stimulatory ligands expressed on antigen-presenting cells (APCs).

• CTLA-4 on T cells can also ligate CD80/CD86 -

• Inhibitory signal
• downregulation
Thank you