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HIS > HIS13 Antigen Recognition By T Cells > Flashcards

HIS13 Antigen Recognition By T Cells Flashcards

1
Q

2 arms of Adaptive immunity

A

Characteristics of adaptive immunity:

  1. Specificity
  2. Diversity
  3. Memory
  4. Discrimination of self vs non-self
  5. Self-regulation

—> Both involve specific antigen receptor

  1. Humoral immunity
    - B cell (BCR)
  2. Cell-mediated immunity
    - T cell (TCR)
    —> Cytotoxic T cell
    —> Helper T cell
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2
Q

***T cell receptor (TCR)

A
  • Heterodimer
  • α + β chains (95% T cells —> conventional T cells)
  • γ + δ chains (5% T cells —> non-conventional T cells —> much lower CDR variability, recognise restricted sets of antigens)

Similar to Ab:
- V domains contain 3 CDRs —> determine Ag binding specificity

Different from Ab:

  • ONLY ***1 Ag binding site per TCR
  • ***NO Fc region
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3
Q

Mechanism for generating TCR diversity

A

Somatic gene recombination of

  1. VDJ gene segments (~ V region of Ig H chain) —> β chain
  2. VJ gene segments (~ V region of Ig L chain) —> α chain

Process similar to gene recombination of Ig V region

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4
Q

***TCR and BCR diversity generation - Comparison

A

Immunoglobulin:

  • Heavy chain —> VDJ (D segments read in 3 frames: Rare)
  • Light chain (κ + λ) —> VJ
  • Total diversity: 10^14

TCR:

  • β chain —> VDJ (β chain often use **3 different reading frames in D gene segment to produce 3 different a.a. sequences —> **generate diversity despite only 2 D gene segments)
  • α chain —> VJ
  • Total diversity: 10^18 (>BCR)

**Differences:
1. NO switch recombination (i.e. **no class switching)
2. NO somatic hypermutation (i.e. ***no affinity maturation)
—> NO changes in TCR sequence in mature T cells
3. NO IgM, IgD expression on surface
4. NO secretory form
—> TCR only exists on T cell surface

Similarities:

  1. DNA recombination of V-region
  2. Junctional diversity
    (3. Transcriptional activation)
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5
Q

How do TCR recognise antigen?

A

BCR / Immunoglobulin:
- Ab protective responses can be transferred from one person to another
—> BUT T cell responses cannot

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6
Q

Relationship between T cell response and MHC

A

MHC: originally identified to initiate transplantation rejection (i.e. Transplantation antigens)

Experiment:
X-infected mouse A
—> T cells taken out and incubate with different cells
1. T cells (mouse A) + X-infected cell (mouse A) —> Good response
2. T cells (mouse A) + X-infected cell (mouse B) —> NO response
3. T cells (mouse A) + Y-infected cell (mouse A) —> NO response

Conclusion:
Antigen recognition by TCR require
1. Specific antigen (must be X-infected)
2. MHC molecules (must be cell from mouse A)
—> **MHC restriction of T cell response: T cell is restricted to recognise a **specific peptide antigen bound to ***self MHC molecules

Doherty and Zinkernagel propose:
1. Dual recognition model
- 2 receptors on T cells
—> 1 recognise viral Ag, 1 recognise MHC separately

  1. Altered-self model
    - TCR recognise MHC molecule modified by viral antigens
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7
Q

TCR complex

A

TCR exists as complex rather than just α/β chains
—> always complex with CD3 complex for intracellular signaling + CD4/8 Co-receptor

Composes of:

  1. TCR α/β chains (Fab region) —> Antigen receptor
  2. CD3 (~ Ig α/β chains with ITAM) —> Signaling complex (δ, ε, γ, ζ chains) possessing ITAM —> Transduce intracellular signals upon Ag binding
  3. CD4 (monomer) / CD8 (dimer) —> **Co-receptor (*B cell無)
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8
Q

TCR Antigen Recognition

A

T cell interact with APC

T cell:

  1. TCR α/β chains —> recognise BOTH peptide antigen + MHC-I/II
  2. CD8/CD4 co-receptor —> aid Ag binding, only recognise MHC-I/II respectively
  3. CD3 complex

APC (Macrophage, B cell, Dendritic cells):

  1. MHC-I / MHC-II (cell surface)
  2. Peptide antigen (presented on MHC-I/II)
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9
Q

2 types of T cells with distinct MHC preference

A

Each MHC molecule constituted by 2 chains

MHC class I
—> α subunit (α1-3) + β2-microglobulin (invariable, not involved in peptide binding groove)
—> Ag peptide binding groove: α1 + α2
—> CD8 co-receptor bind to α3 domain (of α subunit)

MHC class II:
—> α subunit (α1-2) + β subunit (β1-2)
—> Ag peptide binding groove: α1 + β1
—> CD4 co-receptor bind to β2 domain (of β subunit)

(Peptide binding groove: 2 α helices sitting on top of 2 anti-parallel β sheets)

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10
Q

Summary of MHC class I and II comparison

A

In terms of:

  1. Composition
  2. Length of presented peptide
  3. Interacting T cell co-receptor
  4. Expressed by

MHC class I:

  1. **α chain (polymorphic) + **β2-microglobulin (non-polymorphic / invariable: same for every individual)
  2. 8-10 amino acids
  3. CD8
  4. ***ALL nucleated cells

MHC class II:

  1. **α chain + **β chains (both polymorphic)
  2. 12-30 amino acids
  3. CD4
  4. ***APC e.g. macrophages, B cells, Dendritic cells
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11
Q

Major histocompatibility complex (MHC)

A
  • Transplantation antigen —> originally identified as gene region responsible for rejection of tissue / organ transplant
  • Human MHC = Human Leukocyte Antigen (HLA)
  • MHC locus (HLA region)
    —> on short arm of chromosome 6 in human
    —> contain a number of closely linked genes:
    MHC Class I region: A, B, C, E, F, G
    MHC Class II region: DP, DM, DQ, DR
    MHC Class III region: complement 2, complement 4, TNF-α (Cytokine genes, unrelated to antigen presentation)
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12
Q

Isotypes of MHC class I + class II

A

MHC class I:
- α chain (polymorphic)
—> HLA-A, HLA-B, HLA-C —> conventional antigen presentation, polymorphic (記: ABC)
—> HLA-E, HLA-F, HLA-G —> non-classical class I molecules, not for antigen presentation, have other specialised functions, less polymorphic
- β2-microglobulin encoded by separate single gene, non-polymorphic

MHC class II:
- both α + β chain
—> HLA-DP, HLA-DQ, HLA-DR —> antigen presentation (記: PQR)
—> HLA-DM, HLA-DO —> intracellular proteins, not directly associated with antigen presentation, responsible for intracellular loading of peptide to MHC class II molecule

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13
Q

***Diversity of MHC in human

A

MHC diversity achieved by:

  1. ***Polygeny: both class I and II have multiple gene loci in each individual
    - MHC class I: 3 polymorphic classical HLA genes for α chain (i.e. HLA-A, HLA-B, HLA-C)
    - MHC class II: multiple genes for α and β chains (i.e. HLA-DP, HLA-DQ, HLA-DR)
  2. HLA alleles are ***co-dominantly expressed
    - an individual can express 6 different types of MHC class I molecules (3 genes (A, B, C) from Paternal / Maternal HLA haplotype respectively —> each code for 1 molecule)
    - 6-8 different types of MHC class II molecules (DRβ have multiple genes))
  3. Diverse gene ***polymorphism within population
    - MHC class I: HLA-A, HLA-B, HLA-C
    - MHC class II: DRβ gene

簡單而言:

  1. 本身有好多個gene —> 不同種類MHC
  2. Gene一齊express —> 一個cell有multiple MHC molecules on surface
  3. 個gene有好多變化 —> 同一種MHC (e.g. HLA-A)有好多不同version
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14
Q

“Hot spots” of allelic differences (i.e. changes of amino acid sequence)

A 
MHC class I:
- located in α1, α2 subunit
MHC class II:
- located in β1 subunit

Changes in amino acid sequence cause difference in:
1. Charge of peptide binding groove
2. Shape of peptide binding groove
—> affect ***type of peptide being bound to MHC / presented to T cell

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15
Q

MHC polymorphism affects peptide specificity

A
  • Each MHC allele can bind and present distinct sets of peptides
  • MHC polymorphism affects peptide specificity
    —> determines which peptide antigens are bound on MHC molecule
    —> determines whether the peptides can be recognised in different individuals
    —> profound effect on host’s immune response
  • Strong genetic association of MHC polymorphism with many autoimmune diseases and infectious diseases
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16
Q

Antigen processing and presentation

A
  1. Distinct mechanisms for MHC class I and class II presentation
  2. “Empty” MHC molecules are extremely unstable and cannot be found on cell surface without peptides
    —> MHC bounded with self-peptides in normal cells
    —> replaced with foreign-peptides during invasion of pathogens
17
Q

MHC class I presentation pathway

A

***Cytosolic pathway (for proteins in cytosol, self-protein, proteins from intracellular bacteria / virus)

  • Cytoplasmic protein (proteins from bacteria / virus etc.)
    —> **Ubiquitylated protein
    —> cleaved by **    Proteasome into short peptides (~2-10 a.a.)
    —> **Short peptides transported into ER via TAP (Transporter associated with Antigen Processing)
    —> **    Loaded onto MHC class I molecules
  • MHC class I molecules synthesised in ER
    —> stabilised with **chaperone proteins
    —> **    TAP load peptides onto MHC class I (within ER)
    —> chaperone proteins released
  • Finally
    —> MHC-I/peptide complex transported to cell surface via **Golgi bodies
    —> Presentation to **    CD8+ T cell
18
Q

MHC class II presentation pathway

A

***Endocytic pathway (for exogenous proteins, extracellular microbes and antigens)

  • Antigen uptake by **Receptor-mediated endocytosis (e.g. B-cell receptor) / Phagocytosis
    —> enclosed in endocytic vesicles / phagosomes
    —> fuse with lysosomes (containing proteolytic enzymes)
    —> **    Endolysosome / Phagolysosome
    —> protein degradation
  • MHC class II molecules synthesised in ER
    —> folding and stabilised by chaperone proteins in ER
    —> transported in **MHC class II vesicles via Golgi bodies to cytosol
    —> **    fusion of MHC class II vesicles with Endolysosome / Phagolysosome (Antigen中途加入)
    —> loading of digested peptides onto MHC class II molecules (within MHC class II vesicles)
    —> translocation to cell surface
    —> Presentation to ***CD4+ T cell
19
Q

3rd Mechanism: Cross-presentation in Dendritic cells

A
  • Exogenous antigens (MHC class II pathway) can be cross-presented in MHC class I pathway in specialised APC —> ***Dendritic cells (low amount in circulation)
  • Detailed mechanism still unknown
20
Q

MHC expression in various cell types

A

MHC class I:

  • ***ALL nucleated cells (except RBC: no nucleus)
  • amount particularly high in immune cells (B cell, T cell, Macrophage, Dendritic cell, Neutrophil)

MHC class II:

  • ***APC (B cell, Macrophage, Dendritic cell)
  • T cell (only in activated T cell)
  • ***Thymic epithelial cells (for Thymic selection and T cell maturation)
21
Q

Function of APC

A
  1. Capture antigens and migrate to appropriate anatomical site for T cells interaction
    - **T cell activation in Secondary lymphoid organ: Spleen / LN
    - **    T cell maturation + selection in Primary lymphoid organ: Thymus
  2. Display antigens in a form that can be recognised by specific T cells
    - Cytosolic peptides on **MHC class I —> CD8+ T cell recognition
    - Vesicular peptides on **    MHC class II —> CD4+ T cell recognition
  3. Provide “second signals” / co-stimulatory signals for activation of naive T cells
    - B7, CD80, CD86 on APC —> required for activation of naive T cells
22
Q

Antigen presenting cells: Macrophage vs Dendritic cells vs B cells

A

Dendritic cells:

  • Constitutive MHC expression
  • ***Constitutive Co-stimulator delivery —> Very potent in activating naive T cell
  • High uptake of antigens by ***phagocytosis
  • Antigen presented: **Peptides, **Viral antigens, (Allergens?)
  • Location: Lymphoid issue, CT, Epithelium

Macrophage:

  • Inducible MHC expression
  • Inducible Co-stimulator delivery
  • Uptake of antigens by ***phagocytosis
  • Antigen presented: **Particulate, **Intracellular / Extracellular pathogens
  • Location: Lymphoid issue, CT, Body cavities

B cell:

  • Constitutive MHC expression
  • Inducible Co-stimulator delivery
  • Uptake of antigen by ***Ig (antigen-specific receptor)
  • Antigen presented: **Soluble antigens, **Toxins, ***Viruses
  • Location: Lymphoid issue, Peripheral blood
23
Q

Recognition of MHC molecules as Alloantigens

A

Alloantigen:

  • Foreign MHC
  • Refers to MHC (but also include minor histocompatibility antigens)
  • Elicit major immune responses in organ / tissues transplantation mediated by T cell

2 major ways Alloantigens recognised by T cells:

  1. Direct pathway
    - Recipient T cell recognise and activated by ***intact Allo-MHC molecules on Donor APCs (similar but not identical to self MHC)
    - Specificity for the peptide is relatively low (i.e. peptide in this case relatively unimportant, 主角係intact Allo-MHC molecules)
    —> Polyclonal T cell activation / responses
  2. Indirect pathway
    - Recipient APC take up and process Donor antigens (including MHC proteins)
    —> Present Allo-MHC peptides on Recipient MHC molecules to Recipient T cell
    —> Peptide specificity is high (i.e. peptide in this case play a major role)
24
Q

Summary

A

TCR diversity:
DNA rearrangement of V region
- β chain: VDJ gene segments
- α chain: VJ gene segments

MHC diversity:

  1. Polygeny (all expressed)
  2. Co-dominant alleles
  3. Polymorphism

TCR structure:

  1. TCR α/β chains —> recognise BOTH peptide antigen + MHC-I/II
  2. CD8/CD4 co-receptor —> aid Ag binding, only recognise MHC-I/II respectively
  3. CD3 complex

MHC structure:
MHC class I:
- α chain (polymorphic) + β2-microglobulin (non-polymorphic)
- ALL nucleated cells

MHC class II:

  • α chain + β chains (both polymorphic)
  • APC

MHC Class I presentation pathway (Cytosolic pathway):

  • Cytosolic peptides
  • for proteins in cytosol, self-protein, proteins from intracellular bacteria / virus

MHC Class II presentation pathway (Endocytic pathway):

  • Vesicular peptides
  • for exogenous proteins, extracellular microbes and antigens

Recognition of Foreign MHC (Alloantigen):

  • Direct pathway —> 人地完整MHC molecules on 人地APCs recognised by 自己T cell —> Polyclonal T cell activation / responses
  • Indirect pathway —> 自己 APC present 人地MHC peptides to 自己T cell

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