What is a large cluster of genes that encode specialized host cell glycoproteins?
Major histocompatability complex (MHC)
Describe the general function of MHC and how are they related to T cells
some glycoproteins encoded by MHC bind to processed antigens and "present" them on the cell surface
- peptides presented by MHC can be specifically recognized by T cells
Describe the MHC class I molecule
a chain (HC) encoded by MHC has 3 domains; a1&2 form binding site for peptides ; a3 spans membrane of host cell
B2-microglobulin=>small covalently associated chain not encoded by MHC & folds to form Ig-like domain to associate with a3 domain of MHC class Ia chain
T/F Everyone expresses an essentially identical B2-microglobulin
Describe MHC class II
non-covalent association of 2 polypeptide chains
Both a and B chains are glycosylated transmembrane proteins that have 2 domains
- a2 & B2 are similar to Ig domains
- a1 & B1 form a cleft to bind to peptides
Describe the binding groove of each of the MHC molecules
MHC class I molecules are closed on the ends
MHC class II molecules are open on the ends
MHC molecules must be able to bind strongly to a diverse array of peptides that is so strong that it will do what?
bound peptide so tight that it co-purifies with them
With peptide binding recognizing general features, what is the most important part of the binding?
binding cleft of MHC have pockets where AA residues have a particular structure can anchor peptide
the sequence of the peptide is not as important as the position of anchor residues
Describe the peptide binding by the MHC class I molecule
bind to peptides 8-10 AA long and binding groove is closed on each end
stabilized by contacts bw N-terminal and C-terminal ends of peptide and invariant sites found at ends of binding groove
peptide lies an elongated conformation along binding groove
Describe the binding by MHC class II molecules
bind to peptides that are at least 13 residues in length & much longer
ends of the MHC class II binding groove is open ended
MHC class II molecules accommodate longer peptides
What is the degradation of proteins into peptides that can bind to MHC molecules for presentation to T cells?
T/F ALL antigens (except peptides) must be processed into pepties before they can presented via MHC molecules
***Where does antigen processing take place within cells?***
Describe the antigen processing in the cytosol
antigens derived from pathogens that replicate in cytoplasm of cells are degraded into peptide fragments by a proteosome
What is a large cylindrical complexes whose fxn is to recycle cytosolic proteins which they enzymatically chop them into small pieces?
What happens to the peptides that are produced by the proteosome? What complex is needed?
actively transported to the lumen of the ER where they bind to MHC class I molecule
the TAP transporter complex is needed
Describe the TAP transporter complex
TAP transporter complex is an ATP-dependent peptide transporter complex consisting of a TAP1, 2 protein
Peptides from foreign proteins bind to what MHC?
MHC class I molecules
Why are self peptides usually not recognized by patroling CD8 effector cells?
most self-reactive T cells are clonally deleted during the negative selection process in the thymus
only non-self peptides should be recognized by CTLs
Where antigens that are phagocytosed confined to? What happens there?
antigen is degraded by endosomal or lysosomal proteases into peptide fragments
antigens that are confined to endosomal compartment are not available for what?
proteosome for processing
Where are peptide fragments within endocytic vesicles bind to what and transported where?
bind to MHC class II molecules
MHC:peptide complex is transported to cell surface
Peptides generated within endosomal compartments are recognized by what?
recognized by CD4 T cells since they bind to MHC class II molecules
What associates with newly synthesized MHC class II molecules and prevents peptides that are in the ER from bindin in the peptide-binding groove of these molecules?
What happens with the new MHC class II: invariant chain complex?
transported to acidified vesicles where the invariant chain is degraded leaving only the clip peptide attached in the binding groove
A clip protein is associated with what?
Class II-associated invariant chain peptide
Upon interaction with the vesicle membrane protein HLA-DM, the MHC class II molecule does what?
releases clip peptide and then available for binding to peptides within the vesicle
What happens if a peptide does not bind in the clef of the MHC class II molecule quickly?
What if it does bind?
the class II molecule will be degraded
complex is stabilized and exported to surface of the cell for antigen presentation
Name where intracellular pathogens in ANY cell are processed, bound and presented
processed by proteosomes in cytosol of infected cell
peptides bind to MHC I and MHC:peptide complex are transported to surface of cell
peptides are presented to antigen-specific CD8 T cells
Extracellular pathogens (bacteria) are endocytosed by what?
macrophages, dendritic cells, or B cells
Name extracellular pathogens are processed, bound, and presented
endocytosed antigen processed w/in endocytic vesicles
bind to MHC II molecules and MHC:peptide complex is displayed on surface of cell
presented to antigen-specific CD4 T cells
Extracellular pathogen, pathogen-derived antigen or toxin binds to what?
binds to B cell receptor on an antigen-specific B cell
Name where the extracellular pathogen, pathogen-derived pathogen or toxin is processed, bound, presented
endocytosed and processed by the B cell
bound to MHC II molecules and presented on surface of B cell
presented to antigen-specific CD4 T cells
T/F MHC I and II are expressed differentially on cells
MHC class I present peptides derived from what? where? to what?
derived from pathogens
in the cytosol
to either naive or effector CD8 T cells
CD8 T cells are programmed to kill any cell that presents what?
their cognate antigen via MHC class I molecules
MHC class II molecules present peptides produced by what? to what?
produced by processing in endocytic vesicles
to either naive or effector CD4 T cells (T helper)
Where are MHC class II molecules found?
on antigen presenting cells
CD4 T cells are activated by the antigen presenting cells (APC). What is the primary role of these?
to activate other cells of the immune system
Other than APCs, where else are MHC II molecules present on? Why is this important?
present on thymic cortical epithelial cells
important in positive selection of MHC-binding thymocytes durin the thymic maturation process
What does the MHC gene complex encode?
TAP 1, TAP 2
variety of cytokines
several complement proteins
What are teh most polymorphic genes in the mammalian genome?
MHC class I and II
***Describe the 2 properties of MHC that make it difficult for pathogens to evade immune responses in this way***
MHC is polygenic but MHC I and II found on chromosome 6
MHC class I and II genes are highly polymorphic (multiple alleles for each isoform)
What isoforms are found on MHC class I? Where are they expressed?
HLA-A, HLA-B, HLA-C
all expressed on most cells
What are the isoforms of MHC class II? where are they expressed?
HLA-DP, HLA-DQ, HLA-DR
all expressed by most B cells, APCs, thymic epithelial cells
T/F MHC class I and II molecules experience NO rearrangement or somatic alterations occur
Where does the diversity of MHC expression result from?
polygeny(for each individual) and polymorphism (w/in population)
What is a naturally occuring variant of a particular gene?
What is a different form of a protein that is encoded by the alleles of a gene or by different but closely related genes?
For a linked set of polymorphic genes, the set of alleles carried on a single chromosome 6 is what?
What are the 6 isoforms of MHC class I? Which are highly polymorphic and what is their function?
Highly polymorphic: HLA-A, HLA-B, HLA-C => present peptide antigens to T cells
HLA-E, HLA-F, HLA-G
Which MHC I isoforms are oligomorphic and form ligands for NK cell receptors? What immune system is involved?
HLA-E and HLA-G
involved in innate immune responses
What isoform is monomorphic and remains intracellular with unknown function?
What are the 5 isoforms of MHC II? Which are highly polymorphic? What do they present to?
highly polymorphic cells present them to CD4 T cells
Which isoforms of MHC II are oligomorphic and have regulatory roles in peptide loading onto HLA-DP, HLA-DQ, and HLA-DR?
HLA-DM and HLA-DO
T/F MHC II molecules are heterodimeric
What are they composed of?
composed of an alpha chain and a beta chain
Why does a fully heterozygous person express 2 haplotypes of each MHC genes?
each individual expresses both alleles of each HLA gene
What is the minimum number of HLA class I isoforms expressed by an individual? maximum?
3 if homozygous at each loci
6 if heterozygous at each loci
What is the minimum number of HLA class II isoforms? maximum?
Why is this more complicated?
9 with 3 B chains paired w/ 3 different distinct a chains
48 each a and B chain is heterozygous and HLA-DR B chain is inherited on each chromosome => 8 distinct B chains w/ potential to pair w/ 6 a chains
How does the polymorphism affect the peptide binding ability of MHC molecules?
different forms of MHC I and II expressed by different individuals can be highly divergent but still function properly
- ex: differences bw differnt forms of HLA-A are concentrated in regions of MHC molecule taht binds peptide or binds to TCR molecule => alterations in regions of MHC gives rise to differences in peptide binding characteristics of different form of HLA-A => true for each of MHC I and II
Describe transplant rejection
transplanted tissues or organs from donors bearing MHC molecules that differ from those of recipient are reliably rejected
What is the rejection of a graft primarily the result of? Describe this action
result of a potent T cell mediated immune response
- large % of T cells in recipient react specifically w/ particular allogenic (non-self) MHC molecules
Describe graft vs host disease
prior to bone marrow transplant-recipient immune system is destroyed
following transplantation, mature T cells from the donor bone marrow attacks recipients tissues
A transplant bw genetically identical individuals is called what?
syngeneic transplant or isograft
A transplant bw genetically differnet ppl is called what?
allogeneic transplant or an allograft
A transplant from one species into a different species is what?
A transplant of tissue from one area of an individual's body to a different area of the same individual is called what?
T/F T cells ONLY recognize peptides bound to
How is peptide binding of MHC I stabilized?