The major histocompatibility complex and antigen presentation Flashcards
MHC proteins perform a number of functions in the immune response:
- positive selection of T cells in the thymus
- presentation of antigenic peptides to T cells
- The MHC encodes some complement proteins, some cytokines, and proteins involved in antigen processing
- MHC class I and II proteins are also the most important antigens recognized in the graft rejection process
MHC is
a cluster of genes located in close proximity that encode the MHC proteins
Human Leukocyte Antigens (HLAs)
-genes are located on a segment of the short arm of chromosome 6.
MHC is the most ___ gene cluster in the human genome, with large numbers of ____ at several different loci
polymorphic
alleles
alleles
variants of polymorphic genes
Class II MHC locus include
DP
DQ
DR
Class I MHC locus includes
B
C
A
MHC polymorphism is usually detected using ____, hence MHC proteins are often referred to as_______
antibody
major histocompatibility complex antigen
the set of MHC alleles present on each chromosome is called an
MHC haplotype
within a family, there are only ______ haplotypes
4 HLA
Haplotypes from both barents are inherited and expressed_____, each individual expresses the MHC alleles on both chromosomes that are inherited from both parents
codominantly
T or F
MHC proteins are not highly specific for each individual species, hence MHC proteins are considered as species or strain “markers”
F
they are highly specific
Class I MHC molecules consist of
two noncovalently linked polypeptide chains that are constitutively expressed on the cell membranes of most nucleated cells.
Class I MHC are not expressed on
early embryonic life
sperms
neurons
erythrocytes of most mammals
expression of class I molecules on most cell types is enhanced by exposure to _____ such as interferons ___,____, ____.
cytokines
alpha
beta
gamma
Alpha chains
each individual expresses 6 different class I molecules on every cell, containing alpha chains derived from two alleles of HLA-A, HLA-B, HLA-C genes that are inherited from both parents
the alpha chain consist of
- three external domains (alpha1, alpha2, and alpha 3)
- a transmembrane segment
- a cytoplasmic tail
the ______ or groove, located between domains____ and _____ binds peptides containing_____ amino acids
peptide-binding cleft
alpha 1
alpha 2
8-11
a single class I molecule can bind several different antigenic peptides, but_____
only one at a time
the ____ domain contains a loop that serves as the binding site for _______.
alpha 3
T cell coreceptor, CD8
the polymorphic amino acid residues are confined to the
alpha 1and alpha 2 domains
B2m is a _______ (encoded by a gene on chromosome 15) that associates noncovalently with the alpha 3 domain of the alpha chain. It is ___ (nonpolymorphic), ie, all B2m chains of class I molecules are the same
non- MHC-encoded protein
invariant
T or F In the absence of B2m, the class I heavy chain is not expressed on the cell surface
True
the physiologic function of class I MHC molecules is the presentation of peptides derived from proteins in in the ____, eg, _______ to______
cytosol
viral proteins to CD8+ tcell
Class II MHC molecules consist of
two nonidentical protein chains (alpha and beta chains) that are constitutively expressed on the cell membranes of dendritic cells and B lymphocytes, and on activated macrophages
Expression of class II molecules is enhanced by
interferon-gamma
Class II molecules are encoded by three gene regions
HLA-DP
HLA-DQ
HLA-DR
each individual possess about 6 to 12 class II molecules
each of the two chains in MHC II has
- two domains
- a transmembrane segment
- cytoplasmic tail
the polymorphic amino acid residues in MHC II are located where
alpha 1and Beta 1 domains
the peptide-binding groove, formed by interaction of the alpha 1and beta1 domains, binds peptides containing ____ amino acids
10-30 amino acids
T or F a single class II molecule can bind several different peptides (albeit one peptide at a time)
T
a loop in the B2 domains is the binding site for the
T cell coreceptor, CD4
a nonpolymorphic protein called the ___ is associated with newly synthesized class II molecule (plays a role in _______)
invariant chain
antigen presentation
Function of MHC Class II proteins
Class II molecules present peptides derived from protein antigens degrade in cellular vesicles (phagosome or endosome) to CD4+ T cells
in order for class II molecules to be fully expressed they need:
- an alpha chain
- a beta chain
- a bound peptide
within the class II locus are genes that encode several proteins important in antigen processing include:
HLA DM
Proteasome
TAP
HLA DM
facilitates the removal of the invariant chain-derived CLIP protein and the binding of endosomal peptide to class II MHC molecules
proteasome
it is a cytosolic protease complex that cleaves proteins into small peptide fragments that are subsequently by class I MHC molecules
TAP
- transporter associated w/ antigen processing
- transports peptides from the cytosol into the endoplasmic reticulum, where the peptide associate with newly synthesized class I molecules
Class III MHC region
contains genes that code for several complement components, cytokines such as tumor necrosis factor
MHC restriction
the concept that a given T cell will recognize antigen only after it is processed and the ensuing antigenic peptide is bound to a particular class I or II MHC molecule
During T cell development in the thymus, a pre T cell acquires TCR that is specific for both an _____ and _______
antigenic peptide
self MHC molecule
CD8+ T cells
- cytotoxic T cells
- recognize peptide antigen only in association with particular self- MHC class I molecules
CD4+ T cell
- helper T cell
- recognize peptide antigen associated with particular self -MHC class II molecules
certain diseases such as various _____, some _____, certain______, etc, have been associated with the possession of certain MHC haplotypes
allergies
viral infections
auto immune diseases
various hypotheses have been proposed that attempt to explain the relationship between MHC and disease susceptibility include:
- the absence of an MHC molecule that can bind and present an antigenic peptide
- the absence of TCRs that can recognize the complex or antigenic peptide MHC molecule
- The MHC allelic gene may encode molecules that are recognized as receptors by bacterial toxins or viruses
- within a species a reduction in MHC polymorphism may predispose that species to infectious diseases
antigen processing and presentation is defined as
the series of events that result in the conversion of protein antigens to self MHC associated peptide fragments that are then presented to antigen- sensitive T lymphocytes
T or F
T lymphocytes respond only to processed protein antigens
T
the high degree of ___ of MHC class I and II molecules concentrated at the peptide-binding region ensures that a particular species has the potential to effectively respond to and eliminate any antigen encounters
polymorphism.
a single individual expresses a __ number of MHC molecules; this means that_____________ is capable of responding vigorously to each and every pathogen requiring a T cell response for elimination
finite
no single animal or individual
when a peptide binds to an MHC molecule it may stay bound for
hours to several days
MHC molecules bind to and present both _____ and ______ to T cells
self-peptides
foreign peptides
a cell is divided into two compartments
- the cytosol
2. the vesicular system, which includes the endosome, endoplasmic reticulum, lysosomes
cytosolic antigens
antigenic peptides are presented in association with class 1 MHC molecules to CD 8+ T cells
endosomal antigens
antigenic peptides are presented in association with class II MHC molecules to CD4+ T cells
the cells that present peptides associated with class II MHC molecules to helper T cells are called
professional antigen-presenting cells (APCs)
professional antigen- presenting cells
express both class I and class II MHC molecules on their cell membrane
what are the best defined APCs
macrophages
B cells
dendritic cells
dendritic cells
arise from hematopoietic stem cells in the bone marrow and are found in the T cell areas of lymphatic tissues
dendrites
long thin cytoplasmic processes
what is the main job of dendritic cells
they constitutively express many molecules associated with naive T cell activation
T or F
dendritic cells are the most potent stimulators of naive T cell responses
T
dendritic cells also express high levels of the dendritic cell- specific adhesion molecule_____ and also secrete a chemokine called _____ that specifically attracts naive T cells.
DC-SIGN
DC-CK (CCL18)
immature dendritic cells
- called Langerhans cells are found in non lymphoid tissues such as the skin and mucus membranes.
- they are actively phagocytic, however they do not express co-stimulatory molecules
when a protein antigen invades the ___ or ___ , LCs bind the antigen to their surfaces, ___ it onto vesicles and process it. They migrate as ___, via the ___ lymphatics, into the paracortex of the draining lymph nodes, where they mature and become ___________
skin mucosa endocytose veiled cells afferent interdigitating dendritic cells (iDC)
what are interdigitating dendritic cells
mature nonpathogenic cells
what is the role of dendritic cells
capture
processing
presentation
most of the antigen ingested by macrophages is degraded and eliminated by _____; however, some of the peptide products from complexes with MHC class ___ molecules.
exocytosis
II
Macrophages ______ express MHC class II proteins unless they are activated by _____ microorganisms
do not
phagocytosing
Macrophages are beneficiaries of the Th cell effector functions, ie,
cytokines secreted by activated Th cells activate macrophages to kill phagocytosed microbes
B lymphocytes
B cells bind to antigen, using BCR, endocytose them and present processed peptides from the antigens to Th cells. in turn, cytokines produced by effector Th cells stimulates B cells to produce antibodies against antigens
partial degradation of the antigen occurs in the _______, leading to the generation of short peptide fragments of ______ amino acid residues
acidic endosomes
10-20
Antigen processing and presentation steps
- uptake of extracellular proteins into vesicular compartments of APC
- processing of internalized proteins in endosomal/lysosomal vesicles
- biosynthesis and transport of class II MHC molecules to endosome
- association of processed peptides with class II MHC molecules in vesicles
- expression of peptide- MHC complexes on cell surface
Invariant chain( Li CD74)
Newly synthesized class II MHC molecules in the endoplasmic reticulum associate with an MHC class II-associated trimeric invariant chain
when Li chain binds to the class II molecule, part of its polypeptide chain lies within the peptide binding cleft, ensuring that class II molecules_______.
can not bind and present peptides they encounter in the ER
Invariant chain promotes folding and assembly of class II MHC molecules. In its absence, many class II molecules_______________
remain in the eras complexes with misfolded proteins
HLA-DM
this is a specalized MHC class II -like molecule that is found in the MIIC, where it facilitates the lodaing of class II molecules with peptides
what is the main function of HLA-DM
in the MIIc, the Li chain is cleaved by proteases to leave a fragment bound to the peptide groove called CLIP( class II associated invariant peptide). HLA-DM catalyzes the release of CLIP
Additional functions of HLA-DM
- stabilizes the empty class II molecules so they do not aggregate; catalyzes the binding of peptides to the empty peptide groove
- facilitates the release of weakly bound peptides from the peptide grooves and allows other peptides to replace them. this makes sure the APC will survive long enough to encounter the antigen-specific Th cell
- individuals with mutation in the HLA-DM genes, demonstrate defective antigen presentation
T or F If an APC is not processing a foreign antigen, MHC class II molecules are displayed at the cell surface with bound self peptides
T
in order for a immune response to be triggered what two things must happen
- presentation of antigen to naive helper T cell by an MHC class !! molecule on an ApC
- the T cell must be exposed to co-stimulating molecules, such as cytokines and cell membrane proteins, produced by the APC
co stimulatory molecules for helper T cells include:
cytokine interleukin 1 and the cell membrane proteins B7-1 and B7-2
signal 1 leads to the induction of various ____, some of which bind to the _____ of the interleukin-2 and interleukin-2 receptor genes, enhancing their transcription in the T cell. Delivery of the co-stimulatory signal ____ the half life of ____, resulting in IL-2 production. this leads to the ____ and____ of naive T helper cell into effector T cells and memory T cells
transcription factors promotor regions increases IL-2mRNA proliferation and differentiation
signal 2 also induces the synthesis of
anti-apoptotic proteins
in the absence of the co stimulatory signal, the IL-2 mRNA is rapidly degraded preventing the synthesis of _____. as a result, the activation process is terminated and the naive T cell either: fails to respond and die by aptosis
fails to respond and die by apoptosis or enters a state of unresponsiveness called anergy
