Major Histocompatibility Complex

1. Major Histocompatibility Complex (MHC) Molecules
and
Antigen Presentation to T Lymphocytes

2.  Principal functions of T lymphocytes are defense against intracellular
microbes and activation of other cells, such as macrophages and B
lymphocytes.
 All these functions require that T lymphocytes interact with these cells.

3. B cell activation T cell activation
T cell antigen receptors have evolved to see antigens derived from antigens that are
inside cells and are displayed by cell surface molecules. This is in striking contrast to B
lymphocytes, whose antigen receptors and secreted products, antibodies, can recognize
antigens on microbial and host cell surfaces, and soluble cell-free antigens.

4. Features of Major Histocompatibility Complex-Dependent Antigen
Recognition by T Lymphocytes

5.  The Antigen receptors of CD4+ and CD8+ T cells are specific for peptide
antigens that are displayed by Major Histocompatibility Complex (MHC)
molecules.
 The function of MHC molecules is to bind and display peptides for
recognition by CD4+ and CD8+ T cells.
MHC recognition is also required for
the maturation of these T cells, ensuring
that mature T cells are restricted to
recognizing only MHC molecules with
bound antigens.
MHC molecules can bind and display
peptides and no other types of molecules,
and this is why CD4+ and CD8+ T cells
recognize peptides.
MHC molecules are highly
polymorphic, and variations in MHC
molecules among individuals.

6.  There are two main types of MHC
gene products, called class I MHC
(present peptides to CD8+ CTLs)
molecules and class II MHC (present
to CD4+ helper T cells) molecules.
 Antigen-presenting cells display
peptide-MHC complexes for
recognition by T cells and also
provide additional stimuli that are
required for the full responses of the
T cells.
 Different cell types function as
antigen-presenting cells to activate
naive T cells or previously
differentiated effector T cells

7. Functions of different antigen-presenting ce
 DCs are the most effective APCs for activating naive T cells and therefore for
initiating T cell responses.
 Macrophages and B lymphocytes also function as APCs, but mostly for previously
activated T cells rather than for naive T cells.

8. Properties and Functions of Antigen-Presenting Cells
DCs, macrophages, and B lymphocytes express class II MHC molecules and
other molecules involved in stimulating T cells.
These three cell types have been called professional APCs.
All nucleated cells can present peptides to CD8+ CTLs.

9. Routes of Antigen Entry
The common routes through which
foreign antigens, such as microbes, enter
a host are the skin and the epithelia of
the gastrointestinal and respiratory
systems.
Dendritic cells are the cells that are best
able to capture, transport, and present
antigens to T cells.
Classical DCs are present in most
epithelia that interface with the external
environment and are enriched in
lymphoid organs.

10.  The DCs are activated by signals (innate pattern recognition receptors) and by
cytokines, such as tumor necrosis factor (TNF), produced in response to the
microbes.
 By Activation the immature or resting DCs converts to mature cells that are
able to present antigens to naive T cells and to activate the lymphocytes.
Role of dendritic cells in antigen capture and presentation

11. Several properties of DCs make them the most efficient APCs for
initiating primary T cell responses:
 DCs are strategically located at the common sites of entry of
microbes and foreign antigens (in epithelia) and in tissues that may be
colonized by microbes.
 DCs express receptors that enable them to capture and respond to
microbes.
 DCs migrate from epithelia and tissues via lymphatics,
preferentially into the T cell zones of lymph nodes.
 Mature DCs express high levels of peptide-MHC complexes,
costimulators, and cytokines, all of which are needed to activate naive
T lymphocytes.

13.  The MHC was discovered from studies of tissue transplantation in mice.
 Tissues, such as skin, exchanged between nonidentical individuals are rejected.
 The genetic region that controlled graft rejection and contained several linked
genes was named the Major Histocompatibility Complex (MHC).
 In mice this region was named histocompatibility-2, or simply H-2.
 The Human MHC was called human leukocyte antigens (HLA).
 The proteins encoded in the mouse H-2 locus and the HLA proteins identified
in humans had very similar basic structures.
 In the 1960s and 1970s, it was discovered that MHC genes are of fundamental
importance for all immune responses to protein antigens, the relevant genes were
called immune response (Ir) genes.
 It is cleared that Ir genes are, in fact, MHC genes that encode MHC molecules
that differ in their ability to bind and display peptides derived from various protein
antigens.

14. MHC Restriction:
T cell can interact with both
the self-major
histocompatibility complex
molecule and the foreign
peptide that is bound to it, but
will recognize and respond to
the antigen, only when it is
bound to a particular MHC
molecule.
 T cells must be specific not only for the antigen but
also for MHC molecules, and T cell antigen recognition
is restricted by the MHC molecules a T cell sees.

16.  Polymorphism refers to variations in a gene among individuals in a
population. An allele is a variant form of a given gene.
 The MHC locus contains two types of polymorphic MHC genes, the
class I and class II MHC genes, which encode two groups of structurally
distinct but homologous proteins, and other nonpolymorphic genes
whose products are involved in antigen presentation.
 Class I and class II MHC genes are the most polymorphic genes
present in any mammalian genome.
 In the population, the total number of HLA alleles with different
amino acid sequences is estimated to be over 10,000.
 MHC genes are codominantly expressed in each individual.
MHC Genes

17. In human:
 Class I MHC genes: HLA-A, HLA-B,
and HLA-C.
 Class II MHC genes: HLA-DP, HLA-
DQ, and HLA-DR.
Short arm of chromosome 6
Chromosome 17
In mouse:
 Class I MHC genes: H-2K, H-2D, and H-2L
 Class II MHC genes: I-A and I-E

18.  The set of MHC alleles present on each chromosome is called an
MHC haplotype. For instance, an HLA haplotype of an individual could
be HLA-A2, B5, DR3.
 All heterozygous individuals have two HLA haplotypes.
 Class I molecules are expressed on virtually all nucleated cells,
whereas class II molecules are expressed only on dendritic cells, B
lymphocytes, macrophages, thymic epithelial cells, and a few other cell
types.
 This pattern of MHC expression is linked to the functions of class I–
restricted CD8+ and class II–restricted CD4+ T cells.
Expression of MHC Molecules

19. The expression of MHC molecules is increased by cytokines produced during both
innate and adaptive immune responses
Enhancement of class II MHC molecule expression

20. Structure of Class I MHC Molecules
 Class I molecules are composed of a polymorphic α chain noncovalently attached
to the nonpolymorphic β2-microglobulin (β2m).
 The polymorphic residues, which are the amino acids that vary among different
MHC alleles, are located in the floor and walls of this cleft.
Binding site of CD8

21. Structure of Class I MHC Molecules
 Class II molecules are composed of a polymorphic α chain noncovalently attached
to a polymorphic β chain.
 The polymorphic residues are located in the α1 and β1 segments, in and around
the peptidebinding cleft, as in class I MHC molecules.
Binding site of CD4

22.  Most individuals are heterozygous for MHC genes and therefore express
six different class I molecules on every cell, containing α chains encoded by
the two inherited alleles of HLA-A, B, and C genes.
 Each heterozygous individual expresses six to eight pairs of class II MHC
α and β chain molecules, one set each of DP and DQ, and one or two of DR.
Features of Class I and Class II MHC Molecules

23.  MHC molecules show a broad specificity for peptide binding, in contrast to
the fine specificity of antigen recognition by the antigen receptors of
lymphocytes. Very small numbers of peptide-MHC complexes are capable of
activating specific T lymphocytes.
 The peptides that bind to MHC molecules share structural features that
promote this interaction. One of these features is the size of the peptide.
 In addition, peptides that bind to a particular MHC molecule contain amino
acid residues that allow complementary interactions between the peptide and
that MHC molecule.
Peptide-MHC complex

24. PROCESSING OF PROTEIN ANTIGENS
Antigen processing: convert protein antigens present in the cytosol or
internalized from the extracellular environment into peptides and load
these peptides onto MHC molecules for display to T lymphocytes.

25. The class I MHC pathway of antigen presentation
Proteasomes are large multiprotein enzyme complexes with a broad range of proteolytic
activity that are found in the cytoplasm and nuclei of most cells.

26. The class II MHC pathway of antigen presentation
Proteins :extracellular proteins, cell surface proteins, and intracellular proteins that are
routinely included in autophagosomes during the process of autophagy.
Enzyme-containing
vesicles
secondary lysosome
(protease)

27. The functions of class II MHC–associated invariant
chain and HLA-DM

28. Comparative Features of Class I and Class II MHC Pathways of
Antigen Processing and Presentation

29. Cross-presentation of antigens to CD8+ T cells
 Tumor cells or infected cell are ingested by dendritic cells, and the antigens
of the infectious microbes are transported into the cytosol and processed in
proteasomes and presented in association with class I MHC molecules to CD8+
T cells.

30. Presentation of extracellular and cytosolic antigens to
different subsets of T cells

31. Immunodominance of peptides
Immunodominant peptides are the ones that bind best to the available class I
and class II MHC molecules and the majority of the responding T cells are
specific for them.

32.  The best defined of these populations are NKT cells and γδ T cells
 NKT cells express markers that are characteristic of both natural
killer (NK) cells and T lymphocytes and express αβ T cell receptors
with very limited diversity.
 NKT cells recognize lipids and glycolipids displayed by the class I–
like nonclassical MHC molecule called CD1.
 γδ T cells recognize many different types of antigens, including some
proteins and lipids, as well as small phosphorylated molecules and
alkyl amines.