MHC, Antigen Presentation & T - cell activation Flashcards
Organization & Inheritance of MHC
What can Class 1 MHC be found?
And which cell are they presenting antigen to?
Nearly all nucleated cells
Tc cells
Organization & Inheritance of MHC
Where can Class 2 MHC be found?
And what cells are they presenting antigen to?
APC ( Antigen - presenting cells )
e.g. Macrophages, dendritic cells & B cells
Th cells
What is MHC referred to in humans and mice?
Human
-> HLA complex ( human leukocyte antigen )
Mice
-> H-2 complex
Organization & Inheritance of MHC
Can a mouse with MHC haplotype of b/b donate skin to its k/k parent?
Can the same mouse donate skin to its b/b parent?
Can a mouse with MHC haplotype of b/k donate skin to its k/k, b/b parents?
No
Yes
No
MHC molecules / distribution & interaction with peptide
Which of the following antigen will interacts with MHC?
Peptide
Polypeptide
Protein
Glycoprotein
Peptide
MHC molecules / distribution & interaction with peptide
What are the 2 components that make up MHC - 1 distal domain?
Alpha 1 & Alpha 2
MHC molecules / distribution & interaction with peptide
What are the 2 components that make up MHC - 1 proximal domains?
alpha 3 & beta 2 - microglobulin
MHC molecules / distribution & interaction with peptide
Is alpha 1, 2 ,3 part of the same chain?
Yes
What is the meaning of polymorphic?
Which parts of MHC - 1 are polymorphic?
Polymorphic :
Diverse within a population since your parents determines your allele
It adds diversity to a population
Alpha chain is polymorphic
MHC molecules / distribution & interaction with peptide
Where is the peptide - binding cleft located in MHC 1?
Peptide - binding cleft will bind to peptide with how many a.a.?
Between alpha 1 & alpha 2
8 - 10 a.a.
MHC molecules / distribution & interaction with peptide
Is beta 2 - microglobulin encoded by a MHC gene ?
Nope
MHC molecules / distribution & interaction with peptide
What is the 2 components that make up the MHC - 2 distal domains?
Alpha 1 & Beta 1
MHC molecules / distribution & interaction with peptide
What is the 2 components that make up the MHC - 2 proximal parts?
Alpha 2 & Beta 2
MHC molecules / distribution & interaction with peptide
Where is the peptide - binding site located in MHC - 2?
Peptide - binding site will bind to peptide with how many a.a.?
Between alpha 1 & beta 1
13 - 18 a.a.
MHC molecules / distribution & interaction with peptide
Which superfamily is MHC - 1 / 2 classified in?
Ig superfamily
MHC molecules / distribution & interaction with peptide
Which part of MHC - 2 is polymorphic?
alpha 1 & beta 1
MHC molecules / distribution & interaction with peptide
Why is there no genetic rearrangement in production of MHC compared to antibodies production in B cell?
Polymorphic
- MHC varies between individual
-> But one individual produces only one kind of MHC
MHC molecules / distribution & interaction with peptide
How do you calculate the MHC - 1 diversity for an individual?
Since MHC - 1 is solely dependent on alpha chain
Mother MHC - 1 alleles + Father MHC - 1 alleles
E.g.
Mother MHC - 1 alleles : K^k / D^k / L^k
Father MHC - 1 alleles : K^d / D^d / L^d
Kid : Mother + Father = K^k / D^k / L^k / K^d / D^d / L^d
MHC molecules / distribution & interaction with peptide
How do you calculate MHC - 2 diversity for an individual?
Since MHC - 2 diversity depends on an alpha chain & a beta chain
( Mother MHC - 2 alleles + Father MHC - 2 alleles ) x2
E.g.
Mother MHC - 2 alleles : IA a^k b^k / IE a^k b^k
Father MHC - 2 alleles : IA a^d b^d / IE a^k b^d
Kid : ( Mother + Father ) x2
-> IA a^k b^k / IA a^d b^d / IA a^k b^d / IA a^d b^k
-> IE a^k b^k / IE a^d b^d / IE a^k b^d / IE a^d b^k
MHC molecules / distribution & interaction with peptide
Which cell has the highest level of MHC - 1?
Lymphocytes
MHC molecules / distribution & interaction with peptide
Which is anchor residues and the purpose of it?
Which numbers of a.a. are anchor residues?
Which number of a.a. has the highest affinity?
a.a. that are complementary with binding cleft
-> creates a bulge
that looks like this -../.
Anchor residues : 2, 3 ,9
9 ( nomameric peptides ) bind to MHC-1 100-1000 fold higher affinity
MHC molecules / distribution & interaction with peptide
Where does MHC - 1 molecules bind peptides come from?
Endogenous intracellular protein
-> digest in cytosol
MHC molecules / distribution & interaction with peptide
Where does MHC - 2 molecules bind peptide come from?
Exogenous protein
-> Degraded within endocytic processing pathway
MHC molecules / distribution & interaction with peptide
Does both MHC - 1 & 2 bind peptide have anchor residues?
Only MHC - 1 bind peptide anchor residues
Self - MHC restriction of T cell
Can Tc cells kill target cells with different haplotype of MHC - 1?
NOPE
Self - MHC restriction of T cell
What does“ Self MHC, Foreign peptide “ mean?
TCR will only bind with cells with self MHC
TCR will only bind with non self peptide
Antigen - presenting cells & presentation pathways
What is antigen processing & antigen presentation?
Antigen processing :
-> Metabolic process
- -> Degrade protein antigen into peptides
Antigen presentation :
-> Peptide - MHC complexes
- -> Transported to membrane
Antigen - presenting cells & presentation pathways
Which of the following is the most effective APCs?
Dendritic cells
Macrophages
B cells
Dendritic cells
Antigen - presenting cells & presentation pathways
Which of the following must be activated before they become APC?
How are they activated and what do they express after they are activated?
Dendritic cells
Macrophages
B cells
Macrophages
-> Phagocytosis
- -> MHC - 2
- -> B7
B cells
-> Ag - mIg activation
- -> B7
Antigen - presenting cells & presentation pathways
What are the 4 steps in MHC - 1 endogenous pathway?
Degradation of endogenous antigen by proteasome
Peptide -> RER via TAP channel
Binding of peptide & MHC - 1
Peptide - MHC complex [ RER -> Golgi -> Membrane ]
Antigen - presenting cells & presentation pathways
What are the 6 steps of MHC - 2 exogenous pathway?
Invariant chain binds onto MHC - 2 alpha & beta
-> blocks binding of endogenous antigen
MHC complex -> Golgi -> Endocytic pathway compartments
Degradation of Invariant chain
-> leaving CLIP fragment on MHC complex
Exogenous antigen is degraded -> Endocytic pathway compartments
HLA-DM exchanges CLIP for antigenic peptide
Peptide - MHC complex -> membrane
Antigen - presenting cells & presentation pathways
What molecules presents non protein antigens ( e.g. glycolipid )?
CD1
T - cell receptor complex : structure & role
What molecule is responsible for signal transduction and membrane expression of TCR?
CD3
T - cell receptor complex : structure & role
What are 2 molecules that recognize peptide - MHC complex and are responsible for signal transduction?
CD4 & CD8
T - cell receptor complex : structure & role
Which cell has CD4 & which cell has CD8?
CD4 : Th cell
CD8 : Tc cell
T - cell receptor complex : structure & role
What does CD4 bind to & what does CD8 bind to?
CD4 : MHC - 2
CD8 : MHC - 1
T - cell receptor complex : structure & role
Are all TCR made up of alpha& beta chain?
Nope
T - cell receptor complex : structure & role
What are TCR made up of if not alpha & beta?
gamma & delta
T - cell receptor complex : structure & role
What does gamma delta T cells TCR bind to?
Microbial phospholipid
T - cell receptor complex : structure & role
What molecule is used to present antigen captured by gamma delta T cell?
CD1
T - cell receptor complex : structure & role
Are gamma delta T cell related to innate immune system?
Yes
T - cell receptor complex : structure & role
What does gamma delta T cell secrete to recruit alpha beta T cell to the site of invasion?
Cytokines
T cell receptor : organization & expression
In mouse, how many chromosomes are responsible for alpha, delta, beta & gamma chain DNA?
3 in total
-> 14 alpha & delta
-> 6 beta
-> 13 gamma
T cell receptor : organization & expression
In mouse, do both TCR alpha chain & delta chain DNA contain V D J ?
Nope
-> Only delta chain DNA contain VDJ
T cell receptor : organization & expression
In mouse, what happens in alpha delta DNA so alpha beta T cell can be produced?
deletion of delta chain in alpha delta DNA
T cell receptor : organization & expression
In mouse, which of the following has VJ DNA?
alpha chain DNA
delta chain DNA
beta chain DNA
gamma chain DNA
alpha chain
gamma chain
T cell receptor : organization & expression
What is the 5 mechanisms for generating diversity in TCR genes?
( Tips : 4 of them are in BCR diversity too )
V(D)J recombination **
Alternative joining
P - addition **
N - addition **
Junctional flexibility **
T cell receptor : organization & expression
What is alternate joining?
It only occurs in D gene segments
-> Since D genes have One turn RSS on one side and Two turn RSS on another
-> They can join together to increase diversity
-> While joining 3 things can happen to further increase diversity
- -> P - addition
- -> N - addition
- -> junctional flexibility
T cell receptor : organization & expression
Alternative joining can happen on which of the following genes?
Alpha
Delta
Beta
Gamma
Delta
Beta
T cell receptor : organization & expression
How many CDRs are there in TCR?
And what are they called?
3
CDR1, CDR2, CDR3
T cell receptor : organization & expression
Which CDRs in TCR has the most diverse region for antigen recognition? and why?
CDR3 > CDR1 & CDR2
CDR1 & CDR2 are located within V segment
CDR3 is located between the V, (D) & J where many of the diversity mechanisms were applied
T cell receptor : organization & expression
What are the 2 reasons why T cell doesn’t generate a self - reactive response?
T cells who react with self - antigen - MHC are eliminated in thymus
T cells don’t undergo somatic hypermutation
-> T cells specificity don’t change after thymic selection
T cell selection, activation & differentiation
What is the name of the two thymic selection?
What do they do?
Positive selection
-> Thymocytes who bind to self - MHC molecules survives
- -> Thymocytes who don’t have the capability of binding dies
Negative selection
-> Thymocytes that don’t react strongly to self antigen / self - MHC molecules survives
-> Thymocytes that binds strongly to self antigen / self - MHC molecules dies
T cell selection, activation & differentiation
What are the estimated percentage of thymocytes survives & mature?
2%
T cell selection, activation & differentiation
What are the central event in generation of both humoral and cell mediated immune responses?
Activatation
Clonal expansion
T cell selection, activation & differentiation
What does CD3 in TCR - CD3 complex do?
It helps stabilize TCR when TCR binds to antigen MHC complex
& is responsible for signal transmission
T cell selection, activation & differentiation
What is the 2 signals required to fully activate T cells?
Ag - mIg ( TCR - CD3 complex )
CD28 - B7
-> Can be suppressed by CTLA - 4 ( Cytotoxic T - Lymphocyte Associated Protein 4 ) on activated T cell
T cell selection, activation & differentiation
which signal determines clonal anergy or clonal expansion?
Signal 2
-> CD28 - B7
T cell selection, activation & differentiation
Can signal 2 be activated by external help?
(e.g.
-> Another APC reaching out with B7
Yes
T cell selection, activation & differentiation
What are the 3 signal transduction products upon Th cell activation?
And when are they expressed?
( Tips : genes )
Immediate genes
-> Within 30 mins
Early genes
-> 1-2 hours
Late genes
-> After 2 days
