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Infection And Immunity > T cell antigen recognition > Flashcards

T cell antigen recognition Flashcards

1
Q

what are MHC molecules?

A
  • Widely distributed expression
  • Never secreted
  • No effector functions
  • Possess a peptide binding groove
  • Presents processed peptide antigens to T cells
  • Genes are highly polymorphic
  • MHC molecules are so polymorphic that they act as the main foreign antigens in organ transplants
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2
Q

how do T cells recognise antigens?

A
  • Ag Recognised by B cells and antibodies but not by T cells

- Peptide/MHC complexes recognised by T cells

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3
Q

what was the 1st investigation into Immunological tolerance and transplant rejection?

A

Sir Peter Medawer 1915 -1987

Autografts succeed
Allografts fail after initial acceptance
Second grafts - accelerated rejection
The destruction of allografts due to immunological mechanisms

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4
Q

what is IMMUNE GRAFT REJECTION

A

Rejection of transplanted tissue associated with inflammation and lymphocyte infiltration

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5
Q

what is the Genetic basis of transplant rejection?

A

Graft rejection between strains segregates with MHC HAPLOTYPE

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6
Q

what is the Immunological basis of graft rejection?

A

Transplant rejection is due to an antigen-specific immune response with immunological memory.

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7
Q

describe the Distribution of MHC molecules?

A
  1. Patterns of expression reflect function:
    - Class I involved in regulation of anti-virus immune responses all cells can be infected by viruses - all cells express MHC class I
    - Anucleate erythrocytes do not support virus replication - hence no MHC class I.
  2. Class II involved in regulation and development of the immune system
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8
Q

what is the difference in Cleft geometry between classes?

A
  1. MHC class I accommodate peptides of 8-10 amino acids
  2. MHC class II accommodate peptides of >13 amino acids
  3. Peptides are held in the groove by non-covalent forces
  4. Properties of the inner faces of the groove determine which peptides bind
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9
Q

how do we know MHC binding peptides differ in sequence motifs?

A
  • Peptides can be acid eluted from MHC molecules and sequenced
  • Peptides from a particular type of MHC class I molecule have conserved patterns of amino acids
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10
Q

what are MOTIFS?

A

Common arrangements of amino acids in MHC binding peptides

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11
Q

how can MHC molecules bind peptides of different length

A
  1. Complementary anchor residues & pockets provide the broad specificity of a particular type of MHC molecule for peptides
  2. Peptide sequence between anchors can vary
    Number of amino acids between anchors can vary
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12
Q

describe Peptide antigen binding to MHC class II molecules

A
  • Anchor residues are not localised at the N and C termini
  • Ends of the peptide are in extended conformation and may be trimmed
  • Motifs are less clear than in class I-binding peptides
  • Pockets are more permissive
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13
Q

what are ANCHOR RESIDUES ?

A

Amino acids that tether peptides to the MHC molecule

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14
Q

how can MHC molecules bind peptides of different length

A
  1. anchor residues &pockets have broad specificity of a particular type of MHC molecule for peptides
  2. Peptide sequence between anchors can vary
  3. Number of amino acids between anchors can vary
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15
Q

how does Evasion of the MHC by pathogens work?

A
  1. Ag–specific T cells are activated by peptide/MHC complexes
  2. No T cells - no adaptive immunity
  3. Strong selective pressure for pathogens to mutate those nucleotides encoding anchor residues
  4. MHC has strategies to prevent evasion by pathogens
    POLYGENISM - More than one type of MHC molecule in each individual
    POLYMORPHISM - Differences in MHC molecules between individuals
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16
Q

How can the MHC keep up with

rapidly mutating pathogens?

A
  • Allow the population to have many ALLELIC VARIANTS of each type of MHC molecule
  • Accept that the MHC may not protect every individual from every pathogen
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17
Q

how does Evasion of the MHC by pathogens work?

A
  1. Ag–specific T cells are activated by peptide/MHC complexes
  2. No T cells - no adaptive immunity
  3. Strong selective pressure for pathogens to mutate those nucleotides encoding anchor residues
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18
Q

How can the MHC keep up with

rapidly mutating pathogens?

A
  • population has ALLELIC VARIANTS of each type of MHC molecule
  • Accept that the MHC may not protect every individual from every pathogen
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19
Q

how does variation in MHC work?

A
  • type and variant of MHC molecules doesn’t vary in the lifetime of the individual
  • Diversity in MHC molecules exists at the population level NOT in the individual.
  • This contrasts the diversity found in T and B cell antigen receptors which are in a constant state of flux within the individual.
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20
Q

how does Polygeny work?

A

Antigen presenting CLASS I: 3 types HLA-A, HLA-B, HLA-C
Antigen presenting CLASS II: 3 types HLA-DP HLA-DQ HLA-DR
3 extra DR genes in some individuals (CNV) can allow 3 extra HLA-DR molecules
Maximum of 9 types of antigen presenting molecule allow interaction with a wide range of peptides

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21
Q

how does Polymorphism in the MHC affects peptide antigen binding?

A

Changes in amino acids contributing to the pockets, walls and floor of the peptide binding cleft determine which peptides bind.

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22
Q

explain Diversity of MHC molecules in the individual

A

MHC molecules are CODOMINANTLY expressed
Two of each of the six types of MHC molecule are expressed

Genes in the MHC are tightly LINKED and inherited in a unit MHC HAPLOTYPE

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23
Q

how are EXOGENOUS PATHOGENS processed?

A
  • e.g. phagocytksed bacteria & bacteria that survive in cellular vacuoles
  • Eliminated by: Antibodies and phagocyte activation via CD4+ T helper cells
  • Antigens are prepared by EXOGENOUS ANTIGEN PROCESSING
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24
Q

how are ENDOGENOUS PATHOGENS processed?

A
  • e.g. viruses
  • Eliminated by killing of infected cells with CD8+ cytotoxic T lymphocytes (CTL)
  • Antigens prepared for CTL by ENDOGENOUS ANTIGEN PROCESSING
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25
Q

how are EXOGENOUS PATHOGENS processed?

A
  • e.g. phagocytksed bacteria & bacteria that survive in cellular vacuoles
  • Eliminated by: Antibodies and phagocyte activation via CD4+ T helper cells
  • Antigens are prepared by EXOGENOUS ANTIGEN PROCESSING
26
Q

what inhibits lysosomal function ?

A

Chloroquine

27
Q

what are the stages of exogenous antigen processing?

A
  • UPTAKE
    Active introduction to intracellular vesicles
  • DEGRADATION
    Limited proteolysis of antigens to peptides in lysosomes
  • ANTIGEN-MHC COMPLEX FORMATION
    Fusion of lysosomes with MHC containing vesicles
  • ANTIGEN PRESENTATION
    Transport and expression of peptide-MHC complexes on the surface of cells for recognition by T cells
28
Q

describe Uptake of exogenous antigens

A
  • Membrane Ig receptor mediated uptake
  • Complement receptor mediated phagocytosis
  • Phagocytosis
  • Fc receptor mediated phagocytosis
  • Uptake mechanisms direct antigen into intracellular vesicles for exogenous antigen processing
29
Q

describe MHC class II maturation and invariant chain

A
  1. Immature, ‘floppy’ MHC class II in the endoplasmic reticulum
  2. Need to prevent newly synthesised, unfolded self proteins from binding to immature ‘floppy’ MHC
  3. INVARIANT CHAIN stabilises ‘floppy’ MHC class II by non-covalently binding to form a nonomeric complex (αβinv)3
30
Q

what is CLIP?

A

A peptide of the invariant chain, called the CLass II associated Invariant chain Peptide (CLIP) blocks the MHC molecule binding site

31
Q

how does CLIP work?

A
  1. (inv)3 complexes directed towards endosomes by invariant chain
  2. Cathepsin L degrades Invariant chain CLIP blocks groove in MHC molecule
  3. MHC Class II containing vesicles fuse with antigen containing vesicles MIIC COMPARTMENT
32
Q

how does HLA-DM catalyse the removal of CLIP?

A
  1. HLA-DM Replaces CLIP with a peptide antigen by a catalytic mechanism
  2. Discovered using mutant cell lines that failed to present antigen
  3. HLA-DO may also play a role in regulating DM
  4. Peptide-MHC complexes are then exported to the cell surface
  5. Empty MHC and MHC containing CLIP are sent for lysosomal degradation
33
Q

Is exogenous antigen processing enough?

A
  1. Macrophages have well-developed lysosomal systems
    Specialised for motility, phagocytosis and the introduction of particles to thelysosomes
  2. Most cells do not have lysosomal systems as well developed as macrophages
    BUT
    Viruses can infect most cells
    Lysosomal processing is not sufficient to prepare antigens from all pathogens
    A non-lysosomal mechanism to process antigens for presentation to T cells is required
34
Q

why does Non-lysosomal processing require protein synthesis?

A
  • antigens of infectious & inactivated viruses recognised by T cells are generated by different mechanisms.
  • Infectious viruses use cellular protein synthesis machinery to replicate.
  • Inactivated viruses do not synthesise protein.
  • Protein synthesis is required for virus infected target cells to express antigens recognised by CTL
35
Q

why does Non-lysosomal processing require protein synthesis?

A
  • Protein synthesis is required for virus infected target cells to express antigens recognised by CTL
36
Q

how does Degradation in the immunoproteasome work?

A
  1. Cytoplasmic cellular proteins, including non-self proteins
    are degraded continuously by a multicatalytic protease of 28 subunits
  2. The components of the proteasome include MECL-1, LMP2, LMP7
  3. Components are induced by IFN- and displace ‘housekeeping’ components form the ring to confer proteolytic properties.
  4. LMP2 & 7 are encoded in the MHC
  5. Proteasome cleaves proteins after hydrophobic and basic amino acids and releases peptides into the cytoplasm
37
Q

why are Peptide antigens produced in the cytoplasm are physically separated from newly formed MHC class I?

A

Peptides need access to the ER in order to be loaded onto MHC class I molecules

38
Q

what are TAP1 & 2?

A
  • Transporters associated with antigen processing
  • Transporter has preference for >8 amino acid peptides
    with hydrophobic C termini.
39
Q

what happens in Maturation and loading of MHC class I?

A
  1. Calnexin binds to nascent class I chain until 2-M binds
  2. B2-M binds and stabilises floppy MHC
  3. Tapasin, calreticulin, TAP 1 & 2 form a complex with the floppy MHC
  4. Cytoplasmic peptides are loaded onto the MHC molecule and the structure becomes compact
40
Q

how does Evasion of immunity by interference with endogenous antigen processing occur?

A
  1. HSV protein blocks transport of virus peptides into ER
  2. Sent to lysosomes for degradation
  3. Adenovirus protein retains MHC class I in the ER - not exported to the surface
41
Q

what are T cell antigen receptors?

A
  • Only found on T cells - never secreted
  • Always a monomer
  • No effector functions
  • No alternative constant regions
  • Senses the antigenic environment of the T cell
  • Antigen binding site made of Vα and Vβ regions
  • Recognises peptides only in the context of MHC
  • Connects the extracellular environment with signalling pathways
  • Activates T cell effector function
  • Only one antigen specificity per T cell
42
Q

what are the T cell co-receptor molecules?

A

CD4 and CD8 can increase the sensitivity of T cells to peptide antigen MHC
complexes by ~100 fold

43
Q

describe the interaction between TcR, antigen & MHC

A
  1. Vα and Vβ of TcR recognising a peptide from MHC class I

2. αβ TcR recognising a peptide from MHC class II

44
Q

How is diversity generated in TcR?

A
  1. COMBINATORIAL DIVERSITY- Multiple germline segments
  2. JUNCTIONAL DIVERSITY- Imprecise breaking and rejoining of DNA between the V and D genes and the D and J genes creates diversity of sequence and specificity
  3. SOMATIC MUTATION NOT USED TO GENERATE DIVERSITY IN TcR
45
Q

how does diversity arise from TcRα rearrangement by somatic recombination?

A
  • any V gene being able to join to any J gene
  • deliberate errors in breaking and rejoining DNA
  • insertion of new nucleotides between the join
  • NO SOMATIC HYPERMUTATION IN TcR
46
Q

how does diversity arise from TcRβ rearrangement by somatic recombination?

A
  • any V gene being able to join to any D gene and any J gene
  • deliberate errors in breaking and rejoining DNA
  • insertion of new nucleotides between the join
  • Reading rearranged D element in all 3 frames
  • NO SOMATIC HYPERMUTATION IN TcR
47
Q

what are the Steps of Ag receptor gene recombination - TcR & Ig?

A
  1. Double stranded DNA breaks (DSBs)
    - radiation, ROS & mutagens
    - Danger of deletion or translocation of chromosomal fragments - carcinogenesis
    - Cell must exit cell cycle and repair breaks
    Activation of cell cycle postreplication checkpoint
    Repair of DSB by:
    Homologous recombination - sister chromatid acts as a template to create a perfect repair during mitosis.
    Non Homologous End Joining (NHEJ) - broken ends processed to be compatible for ligation - genomic integrity may be lost.
  2. V(D)J recombination
    T and B cell restricted mechanism that causes deliberate DSB between V(D)J elements
    Repair DSB with a widely expressed DNA repair mechanism - NHEJ
48
Q

what are the Lymphocyte specific events involving RAG1 & 2?

A
  1. Recombination activating gene products, (RAG1 & RAG 2 - expressed only in T and B cells) and ‘high mobility group proteins’ bind to the RSS
  2. The RAG complex induces synapsis of the V and DJ regions: The two RAG1/RAG 2 complexes bind to each other and bring the V region adjacent to the DJ region
49
Q

what are the Lymphocyte specific events involving deliberate creation of DSBs?

A
  • The recombinase complex makes single stranded nicks in the DNA
  • The 3’OH created by the nick attacks a phosphodiester bond on the unbroken strand
  • forms a sealed hairpin structure at the end of the V and D regions and a flush double strand break at the ends of the heptamers
50
Q

how does the NHEJ mechanisms start to repair the DSBs?

A
  1. Ubiquitous NHEJ repair proteins, Ku70 and Ku80 heterodimerise and bind to the DNA break.
  2. Ku70:Ku80 acts as a scaffold for DNA dependent protein kinases (DNA-PK) and the nuclease, Artemis.
  3. Artemis opens the hairpins at the end of the V and D regions. (The RAG complex, Ku70:Ku80 complex and DNA PK:Artemis complex remain associated with the DNA break)
  4. Exonucleases and transferases now start to process the DNA ends at the CODING JOINT. This is the stage at which JUNCTIONAL DIVERSITY is introduced.
51
Q

how does the The discarded loop signal Joint formation work?

A
  1. DSB on non coding portion are dangerous and have to be ‘neutralised’.
  2. Ku70:Ku80 remains associated with DSB at the SIGNAL JOINT.
  3. no exonuclease or transferase processing or modification at this break.
  4. A complex of DNA ligase IV and XRCC4 binds to the DSB
  5. The ends are ligated to form a circle of DNA that is permanently lost from the genome.
  6. The loop of excised DNA may contain several unused V (or D or J) elements that the T (or B) cell will never be able to recover.
52
Q

how is Junctional diversity achieved with P nucleotides TcR & Ig?

A
  1. The RAG1:RAG2 recombinase complex makes single stranded nicks at random sites close to the ends of the V and D region DNA.
  2. The exposed 3’OH group attacks a phosphodiester bond on the unbroken strand and forms hairpins form between the at ends of the V and D region.
53
Q

how does Generation of the palindromic sequence work?

A
  1. Regions to be joined are juxtaposed and Ku70:Ku80 complex is formed around the DSB.
  2. DNA-PK:Artemis complex binds to the Ku70:Ku80 complex.
  3. Artemis nuclease cleaves single strand at random sites in V and D segment to open the hairpin.
  4. The nucleotides derived from the top/bottom DNA strand are now part of the bottom/top DNA strand respectively.
  5. In terms of G to C and T to A pairing, the ‘new’ nucleotides are palindromic.
  6. The nucleotides GA and TA were not in the genomic sequence and introduce diversity of sequence at the V to D join
54
Q

how do N nucleotides help junctional diversity in TcR & Ig

A
  1. Terminal deoxynucleotidyl transferase (TdT) adds nucleotides randomly to the P nucleotide ends of the single-stranded V and D segment DNA
  2. Complementary bases anneal
  3. Exonucleases nibble back free ends
  4. DNA polymerases fill in the gaps with complementary nucleotides and the DNA ligase IV:XRCC4 complex joins the strands
55
Q

summarise Junctional Diversity in TcR and Ig

A
  1. Germline-encoded nucleotides
  2. Palindromic (P) nucleotides - not in the gremlin
  3. Non-template (N) encoded nucleotides - not in the gremlin
  4. Creates an essentially random sequence between the V region, D region and J region in beta chains and the V region and J region in alpha chains.
56
Q

Why is there no somatic hypermutation in T cell receptors?

A
  1. prevents T cell help to autoreactive B cells
  2. B cell specific for non self AgX somatically mutates in the germinal centre to become specific for AgY - a self antigen
  3. AgY specific T cells must provide help to AgY specific B cells to clonally selected & make antibody - otherwise they die by neglect.
  4. BUT…AgY specific T cells were removed from the T cell repertoire by the mechanisms of immune tolerance to self.
  5. If TCR were able to somatically mutate, anti-AgY T cells could emerge after self tolerance has been established. Anti-AgY T cells would then be able to help the anti-AgY B cell to make autoantibody.
57
Q

why is there Somatic hypermutation in B cell receptors?

A
  1. To capture and maintain complexes with toxins from the fluid phase
  2. To increase the affinity of these interactions throughout an immune response
  3. There is a powerful selective advantage to B cells that can somatically mutate their receptors
58
Q

how would a Somatic mutation in TCR cause a T cell to be useless or harmful?

A
  • TCR interacts with entire top surface of MHC-peptide antigen complex, not just peptide antigen
  • Somatic mutation in TcR might change the amino acids that interact with MHC molecule resulting in either:
    1. a complete loss of MHC recognition - USELESS
    2. too much recognition of the MHC - HARMFUL
59
Q

whats the difference between MHC 1 and 2?

A

1- on nucleated cells, long a chain short B, interact with cytotoxic T cell
2. present on ag presenting cells, 2 identical chains a+b, interact with t helper cells.

60
Q

MHC has strategies to prevent evasion by pathogens?

A

POLYGENISM - More than one type of MHC molecule in each individual
POLYMORPHISM - Differences in MHC molecules between individuals

Infection And Immunity (16 decks)

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