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IC2: Antibody and T cell therapy > Ab, T cell receptor, MHC > Flashcards

Ab, T cell receptor, MHC Flashcards

1
Q

Antibody monomer is composed of _ polypeptide chains and encoded by _ genes

A

4 polypeptide chains (2 identical light chains and 2 identical heavy chains)
Encoded by 2 genes

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2
Q

Fc domain of an antibody molecule is responsible for biological activity mediation via immune triggering module function

Describe the 2 biological effector functions that the Fc domain is involved in

A
  1. Antibody dependent cellular cytotoxicity
    (Fc domain binds to macrophages, NK cells, neutrophils via Fc receptor found on these effector cells surfaces)
    *Fc domain exists in another conformation until Fab gets bound to an antigen, after conformational change, Fc domain can now bind to Fc receptor
  2. Complement-dependent cytotoxicity
    (Bind to complement proteins in bloodstream, antibody able to kill)
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3
Q

What is the role of cysteine residues forming S-S disulfide bonds in antibody and T cell receptor respectively?

A

Antibody: interchain and intrachain disulfide bond to ensure correct 3D conformation such that Fab domain can recognize epitope, and Fc domain can recognize Fc receptor
*Note that other non-covalent bonds exist between AA along both light and heavy chain as well

T cell receptor: cysteine residues form disulfide bond to link up the alpha and beta chains in the extracellular constant region

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4
Q

Which domain of an antibody undergoes post-translational modification

A

Fc domain undergoes glycosylation (additional of carbohydrate chain)

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5
Q

How many Complementarity-determining region (CDR) in each Fab arm?

A

6 CDRs (3 from VL domain, 3 from VH domain)
*6 CDRs form 1 paratope

Each antibody monomer has 2 Fab arms and 1 Fc arm
Hence, each antibody monomer has 12 CDRs from the hypervariable domains in the heavy and light chains

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6
Q

Describe the 3 properties of an antibody

A
  1. Antigen affinity: strength of interaction b/w antibody and antigen at a single antigenic site
  2. Antibody specificity: goodness of fit between paratope and antigenic determinant
    *Low specificity antibody will display cross-reactivity (bind to more than one different epitope)
  3. Antigen Avidity: strength with which an antibody binds to its target, if the target contains multiple antigenic sites/epitopes
    E.g., IgM has poor affinity at single sites, but high avidity (it is a pentamer with 10 Fab arms)
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7
Q

How many genes encode for a TCR?

A

2 genes - 1 for alpha chain, 1 for beta chain

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8
Q

Describe the 3 domains/regions of a TCR

A
  1. Two extracellular domains (glycosylated) - variable region and constant region
    *Variable region has 6 CDRs
    *Constant region has disulfide bonds
  2. Transmembrane region - across plasma membrane
    *AA sequence of alpha and beta chain should be hydrophobic so as to interact with phospholipid bilayer
  3. Short cytoplasmic tail - inside cytoplasm
    *Insufficient to activate T cell and mediate signal transduction upon antigen binding
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9
Q

How does TCR resemble one Fab arm?

A

1 Fab arm: 3CDRs in VL, 3CDRs in VH
TCR: 3 CDRs in Va, 3CDRs in Vb

The CDRs are responsible for antigen recognition and binding

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10
Q

TCR complex consists of CD3 adaptor proteins

How many invariant CD3 dimers make up the octameric complex in the plasma membrane?

A

3 invariant CD3 dimers (CD3εγ, CD3εð, CD3ζζ)

aka

6 CD3 monomers that dimerize to form 3 invariant dimers

*a and B chains in TCR associate with 3 invariant dimers that form an octameric complex in the plasma membrane

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11
Q

There are 10 immunoreceptor tyrosine-based activation motif (ITAMs) in each TCR complex. Describe the function.

A

Each monomer has 1 ITAM, except CD3ζ has 3 ITAMs
*ITAMs are critical AAs in the intracellular domain of the TCR complex

Function:
Upon TCR-antigen binding in the extracellular domain, trigger changes within the receptors such that intracellular components can mediate signal transduction
Tyrosine residues in ITAMs get phosphorylated (PTM) and initiates a series of downstream T cell signalling events, leading to T cell activation

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12
Q

what does ITAM stand for

A

immunoreceptor tyrosine-based activation motif

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13
Q

After rearrangement of immunoglobulin genes in the bone marrow, immature B cells with surface immunoglobulins/B cell antigen receptors leave the bone marrow and are found in circulation and secondary peripheral lymphoid tissues. What happens after encounter with pathogenic antigens?

A
  1. Gene arrangement in Fc domain (class switching) e.g., IgM to IgG
  2. Gene rearrangement in the VH and VL regions in the Fab domain so that diff hypervariable CDR confer diff antigen specificity

*Do note that in bone marrow rearrangement prior to/independent of antigen exposure, immature B cells already have hypervariable CDRs recognizing diff epitopes

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14
Q

How is TCR diversity obtained prior to antigen exposure?

A

Genetic recombination of DNA segments in genes encoding the Va and Vb regions of the TCR gives rise to unique combination of the segments for each recombined TCR expressed by an immature T cell

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15
Q

Describe the genetic recombination of DNA segments encoding the Va and Vb regions respectively

A

Va: VJ recombination gives rise to CDR1a, CDR2a, CDR3a

Vb: VJ recombination, followed by VDJ recombination, gives rise to CDR1B, CDR2B, CDR3B

*Ca and Cb regions of the TCR are constant regions, and hence these DNA segments do not undergo recombination

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16
Q

What is the role of hypervariable CDR in antibodies and TCR?

A

Responsible for diversity, which in turn allows for antigen specificity

17
Q

What is the function of MHC molecules?

A

They are cell surface proteins that bind to peptide (antigenic) fragments and display them for recognition by T cells

Link between innate and adaptive immunity

18
Q

peptide-MHC II (pMHC II) on cell surface is presented to ______

This is important as _______

A

CD4+ helper T cells

Initiate full adaptive immune response through the production of humoral component cytokines etc. that can activate other cytotoxic T cells and B cells

19
Q

MHC region are divided into __ subtypes

Only Class _ and _ are involved in antigen presentation (have immune functions)

A

*MHC region is a family of >200 genes located on chromosome 6

MHC region are divided into 3 subtypes

Only Class I and II are involved in antigen presentation (have immune functions)

20
Q

MHC class I is present in:

A

All nucleated cells and platelets

NOT present in RBC (since no nucleus)

21
Q

MHC Class II is present in:

A

APCs - macrophages, dendritic cells

B cells (meaning B cells can present to CD4+ T cells as well)

22
Q

Normal self-antigens, neoantigens, and viral antigens are presented by which MHC class molecule?

A

MHC Class I molecules present endogenous antigens

23
Q

Peptide-MHC I expressed on cell surface can be presented to ____ and _____

A

CD8+ cytotoxic T cells and natural killer cells

(self-antigens presented to NK cells - lack of inhibitiory MHCI or incr activating ligands cause activation of NK cells)

24
Q

What are proteasomes?

Which MHC Class molecule involves proteasome in its mechanism of presentation?

A

Protein complex present in cells to degrade unwanted/damaged proteins by proteolysis. Consists of proteases that cleave peptide bonds to peptide fragments of ~15 AA

Cytosolic (intracellular) proteins are transported to proteasomes in cells that ultimately release antigen-MHC Class I complex for recognition by CD8+ T cells

25
Q

What is the mechanism of presentation of MHC Class I molecules?

A
  1. Intracellular cytosolic proteins transported to proteasome, where proteases/peptidases are present to cleave peptide bonds (proteolysis)
  2. Small peptides delivered into endoplasmic reticulum by TAP transporter
  3. TAP interacts with MHC class I molecules in the endoplasmic reticulum, which is linked to several helper proteins
  4. When MHC Class I molecule permanently binds to one of the peptide fragments, TAP transporter and helper proteins dissociate
  5. Antigen loaded MHC Class I molecule is pinched off into a vesicle and migrates through the Golgi apparatus to cell surface for fusion with the plasma membrane
  6. Release of antigen-MHC Class I complex
26
Q

What is the mechanism of presentation of MHC Class II molecules?

A
  1. Exogenous antigens taken up via endocytosis into endosomes
  2. In early endosomes, antigens are degraded by proteases to peptide fragments
  3. Peptides interact with MHC Class II molecules in MIIC (MHC class II compartment)
    *The MHC class II molecules travel from endoplasmic reticulum into MIIC
  4. Helper protein in MIIC (late endosome) removes small molecule that is blocking the binding site of MHC Class II molecule, and exchanges it for an antigen
  5. Vesicle travels to cell surface and fuses with plasma membrane
  6. Present antigen-MHC Class II complex on cell surface
27
Q

How is the endoplasmic reticulum involved in both MHC Class I and Class II antigen presentation?

A

Processing of pMHCI and pMHCII involves ER as MHCI and MHCII molecules are found in the ER

28
Q

CD8+ T cells express CD8 receptor + TCR
CD4+ T cells express CD4 receptor + TCR

What do each of the receptor bind to?
*TCR consists of CDR1, CDR2, CDR3 in Valpha and Vbeta, what do each of these bind to?

A

CD8/CD4 receptor bind to MHCI/MHCII molecule present in the pMHC proteins respectively, to bring proximity to the TCR

TCR: binds to antigenic peptide + MHC molecules
CDR1 - bind to each terminus of the peptide in pMHC
CDR2 - bind to MHC in pMHC
CDR3 - bind to peptide in pMHC

29
Q

How is the level of MHC molecule expression regulated?
(Level of MHC molecule expression affects the extent of T cell activation)

Describe action of IFNa and IFNy

A

By humoral components - e.g., cytokines

IFNa (produced by leukocytes): incr transcription and expression of MHC molecules (upregulates immune system, antiviral action)

IFNy (produced by T lymphocytes): induces macrophages to increase expression of MHC molecules (immunomodulatory cytokine)

*IFNy also induces macrophages to express cytokines and Fc receptors

30
Q

What are the 2 characteristics of MHC molecules?

What is the purpose of these characteristics?

A
  1. Polygenic - diff MHC Class I and Class II genes, therefore express diff sets of MHC Class I and Class II molecules that possess diff peptide binding specificities
  2. Polymorphic - each MHC gene have diff alleles, can differ up to 20 AAs (usually at the peptide binding domains of MHC molecules)

Purpose: diff sets of MHC molecules are able to present diff antigens to T cells, allow broader coverage against diff antigens

IC2: Antibody and T cell therapy (3 decks)

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