Exam II Flashcards
what is antigen processing?
series of intracellular events in which antigen presenting cells make antigen available for T cells
Antigen processing involves
- Uptake of antigens (proteins)
- Degradation to peptides of MHC I or II
- Transport to the cell surface
what is antigen presentation?
Presentation of MHC peptide complexes on the cell surface for the stimulation of T cells
Typically done by antigen presnting cells (APC)
1. Dendritic cells
2. macrophages
3. B cells
Types of APC?
Dendritic Cells
Macrophages
B cells
T cell receptor binds to both
peptide and MHC molecule
T cells must have
MHC in order to be able to respond to an antigen
Cytotoxic T cells
CD8
CD8 complex consists of
alpha and beta
Helper T cell
CD4
CD8 T cell, their T cell receptor binds to
alpha3 domain of MHC class I
CD4 T Cell, their T cell receptor binds
Beta2 domain of MHC class II
Endocytic processing pathway
Exogenous (antigens from outside the cell) or MHC Class II processing pathway
Bound to MHC Class II and taken into the cell
Cytosolic
Endogenous (proteins that exist in the cytoplasm) or MHC Class I processing pathway
Endocytic Pathway
- Antigen is taken up from the extracellular space into intracellular vesicles
- In early endosomes of neutral pH, endosomal proteases are inactive
- Acidification of vesicles activates proteases to degrade antigen into peptide fragments
- Vesicles containing peptides fuse with vesicles containing MHC Class II molecules
The MCH class II binds to the peptide.
lower pH, more degradation
MHC II molecule is synthesized in
lumen of ER
How MHC class II gets to the processed peptides
- Invariant chains blocks binding of peptides to MHC class II molecules in the ER
- In vesicles, invariant chain is cleaved, leaving the CLIP fragment bound
- CLIP blocks binding of peptides to MHC Class II in vesicles
- HLA-DM facilitates release of CLIP, allowing peptides to bind
MHC Class II - endocytic
presents peptide antigens
Invariant chain - endocytic
directs class II away from secretory pathway to endocytic pathway and blocks peptide loading in the ER
HLA-DM -endocytic
acts as a chaperone or catalyst to facilitate exchange of CLIP with antigenic peptides
pH - endocytic
low pH and degradative environment facilitates denaturation of antigenic proteins
proteases - endocytic
cathepsins and other degradative enzymes chew up antigens into peptides
Cytoplasmic pathway (antigens are in the cytoplasm)
proteasome - degrades the antigen protein into peptides,
- class I is heavy chain is stabilized by calnexin until B2-microglobulin binds
- Calnexin is released and the heterodimer of class I heavy chain and b2m forms the peptife loading complex with calreticulin, tapasin, TAP, ERp57, PDI
- A peptide delivered by TAP binds to the class I heavy chain, forming the mature MHC class I molecule
TAP (I and II)- transport port through the ER membrane.
- The class I molecule dissociates from the peptide loading complex and is exported from the endoplasmic reticulum
MHC class I protein
alpha chain (3 domains) - transmembrane protein
beta 2 microglobulin - associated with all MHC 1 - stabilizes it.
peptides that are produced in the cytosol are transported into the ER
Peptides re generated in the cytoplasm and then transported through TAP into the ER and associate with MHC class I
MHC class I - cytosolic
presents antigenic peptides to T cells
proteasome - cytosolic
multi catalytic enzyme complex that degrades proteins into peptides
TAP - cytosolic
transport that shuttles peptides from cytosol to ER
peptide loading complex - cytosolic
calnexin, calreticulin, tapasin, Erp57: stabilize MHC class I and facilitate association with TAP to enable peptide loading
site where MHC II gets loaded with peptides
endosome
site where MHC I gets loaded with peptides
ER
Cytosolic pathogen
- Degraded in:
- peptides bind to:
- Presented to:
- Effect on presenting cell
Degraded in - cytosol
Peptides bind to - MHC I
Presented to - effector CD8 T cells
Effect on presenting cell - cell death
Intravesicular pathogens
Degraded in:
- peptides bind to:
- Presented to:
- Effect on presenting cell
Degraded in: endocytic vesicle (low pH)
Peptides bind to: MHC class II
Presented to: Effector CD4 T cell
Effect on presenting cell: Activation to kill intravesicular bacteria and parasites
How T cell receptors bind to MHC
They do directly bind to MHC molecule -> Polymorphic reside of MHC and T cell contact reside of peptide
But
they also have direct contain with the peptide bound to MHC. T cell contact reside of peptide
- “pocket of MHC”
Major histocompatability complex (MCH)
refers to the complex of genes that encode molecules on the cell surface that:
- mediate T cell reactivity to pathogen infection -> present peptides derived from pathogens to T cells)
- Compatability of organ transplants
- susceptibility to certain autoimmune diseases
Known as HLA in humans and H-2 in mice
divided into three groups: MHC class I, II and III
HLA
Human Leukocyte Antigen
MHC class I structure
Peptide binding cleft: alpha 1+ alpha 2
1 Transmembrane domain
Associates with beta2Microglobulin (always)
CD8 binds to alpha3
MHC class II structure
Peptide binding cleft: alpha 1+ beta 1
alpha 2 and beta 2 are distal from the binding cleft
2 transmembrane regions
CD4 binds to beta 2 domain.
Difference in structure of MHC I and II
I - beta chain is not a transmembrane protein
II - beta chain is a transmembrane protein
Both MHC I and II consists of a
base of beta pleated sheets
and walls are formed of 2 alpha helices.
MHC class I - restricted
strict binding site, allows peptides of 8-10 aa in length
MHC class II - flexible
flexible peptide binding site allows peptides of 10-24+ aa in length
Where is the variablility?
MHC I - peptide binding cleft on both beta pleated sheets and alpha helices
MHC II - majority is in the beta chain. both alpha helix and beta pleated sheets
MHC is both
polymorphic - every gene locus, more than one allele
polygeny - many different MHC molecules/genes expressed
genetic polymorphism
variants or alternative forms of a gene present in a population at a stable frequency
allele
one type of variant
homozygous
having two identical alleles of the same gene
heterozygous
having two distinct alleles of the same gene
haplotype
the collective set of MHC alleles present on an individual chromosome
Human types of MHC class I isotypes
Highly polymorphic
HLA - A
HLA - B
HLA - C
Human MHC Class II isotypes
Polymorphic
HLA - DP
HLA - DQ
HLA - DR (Oligomorphic + highly polymorphic)
Which HLA is the most polymorphic
HLA-B
Which MHC class is most selective?
MHC class II
BCells, macrophages, dendritic cells only. but these cells are also expressed by class I