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micr 386 > module 03 section 04 (TCR complex) > Flashcards

module 03 section 04 (TCR complex) Flashcards

1
Q

what is the goal of T-cell development?

A

to generate mature, functional T-cells bearing TCRs that are capable of recognizing a broad range of antigens in the context of self-MHC

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2
Q

where does the development of mature T-cells from progenitor T-cells take place?

A

the thymus

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3
Q

mature T-cells express a heterodimeric TCR that is composed of __(1)__ or __(2)__

A

(1) one alpha and one beta chain

(2) one gamma and one delta chain

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4
Q

when progressing through development, progenitor T-cells undergo: (4)

A

lineage commitment, TCR gene rearrangements, proliferation and selection

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5
Q

are TCR heterodimeric domain structures classified as members of the Ig family? why or why not?

A

yes - structures are simialr to those of the Igs

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6
Q

what do all TCR chains contain in the extracellular domain?

A

2 Ig chains that are structurally homologous to the variable and constant chain domains of the Igs

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7
Q

how many domains does the membrane bound TCR consist of?

what are they?

A

3 - extracellular, transmembrane and cytoplasmic

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8
Q

what is the extracellular domain of the membrane bound TCR

A

heterodimer of a&b or g&d

but most have the TCR-ab heterodimer

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9
Q

how are the two heterodimer chains of the extracellular domain of TCR linked?

A

covalently by disulfide bonds

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10
Q

on each extracellular domain, TCR expresses:

A

oligosaccarides (CHO)

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11
Q

do T-cells expressing the TCR-gamma/delta heterodimer have a hightened or restricted ability to recognize antigens?

why?

are there any exceptions?

A

restricted - these cells lack CD4 and CD8 molecules on their surface
**except intraepithelial lymphocytes

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12
Q

where are intracellular lymphocytes?

what receptor do these cells express?

A
  • subset of T-cells that are located in the gut epithelium

- express CD8+

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13
Q

what are the first lymphocytes to arise during development in the fetus?

A

intraepithelial lymphocytes - play a critical role in protection agaisnt infections

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14
Q

what is the funtion of the transmembrane domain of TCR?

A

to anchor TCR to the cell membrane together with the CD3 complex

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15
Q

what is the result when TCR lacks a cytoplasmic domain?

A

makes the TCR unable to trigger a singal by itself for cell activation

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16
Q

explain the cytoplasmic domain

A

TCR a/b and g/d are closely associated with the invarient proteins of the CD3 complex

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17
Q

what is the function of the cytoplasmic domain of TCR?

A

(1) signalling and cell activation (primary function)
(2) TCR assembly and expression on the cell surface
(3) stabilizing the TCR on the cell membrane

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18
Q

what does the CD3 complex consist of?

A

5 polypeptide transmembrane chains expressed as dimers: epsilon/delta, epsilon/gamma and sigma/sigma

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19
Q

what is required to interact for a signal to be transmitted by the TCR?

A

co-receptors

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20
Q

what are the 2 T-cell co-receptors expressed on a mature cell?

A

CD4 and CD8

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21
Q

what is the structure of a CD4 co-receptor?

A

monomer with 4 domains, structurally similar to Ig domains

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22
Q

what are 2 characteristics of the CD4 receptor?

A

(1) marker for helper T-cells

(2) D1 and D2 domains bind to a conserved site on the B2 domain of the MHC class II molecules on APCs

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23
Q

what is a clinical application of CD4 receptors?

A

HIV binds to CD4 to infect CD4+ helper T-cells

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24
Q

what is the structure of a CD8 co-receptor?

A
  • aB heterodimer or aa homodimer
  • chains are covalently attached by a disulfide bond
  • has 1 Ig fold
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25
Q

what are 2 characteristics of the CD8 receptor?

A

(1) marker for cytotoxic T-cells

(2) binds to a site at the base of the a3 domain of MHC class I molecules on APCs

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26
Q

what determines the lineage of TCR gene rearrangement?

A

gene silencer elements embeded in the TCR gene segment

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27
Q

what are the two lineages that TCR gene rearrangement can commit to ?

A

alpha/beta or gamma/delta

28
Q

explain the process of TCR rearrangement

A

start with TCR-γ,

(1) then if γ-silencers are turned off, the VDJ rearrangement occurs in the γ chain, then the VJ rearrangement happens in the δ chain, leading to the production of TCR-γδ
- 1-5% of cells express this
(2) if γ-silencers are on, the VDJ rearrangement occurs in the β chain, the VJ rearrangement occurs in the α chain, leading to the production of TCR-αβ

29
Q

once the α-VJ rearrangement has completed, what happens to the δ gene segment?

A

it’s deleted

30
Q

how does TCR antigen specificity arise?

is this simialr or different to B-cell receptor specificity?

A

similar to b-cell receptors, TCR antigen specificity is the result of gene rearrangement

31
Q

where is the mouse TCR-γ chain DNA located?

A

chromosome 13

32
Q

explain TCR-γ chain gene rearrangement

A

it involves the joining of Vγ to Jγ forming the VJγ

33
Q

what happens after TCR-γ gene rearrangement?

A

transcription and splicing of the VJγ exon to Cγ genes generates mRNA - which is then translated to yeild the TCR-γ chain

34
Q

in addition to γ-silencers, what is another important structure involved in determining TCR gene rearrangement?

A

pseudogenes

35
Q

what is a pseudogene

A

a nonfunctional gene due to mutation

36
Q

how is the mRNA that is translated to yeild TCR β/α/… chain generated?

A

transcription and splicing of the VDJβ (VJα) exon to Cβ(α) generates the mRNA that is translated to yeild the TCR-β(α) chain

37
Q

how can cells with nonprodutive VDJβ rearrangements in the Cβ1 locus be rescued?

A

ONLY by a subsequent rearrangement in the Cβ2 locus

38
Q

describe how subsuquent rearrangement in the Cβ2 locus can rescue nonproductive rearrangements in the Cβ1 locus

A

involves another Vβ gene segment rearranging to a DJβ segment in the Cβ2 locus, deleting the Cβ1 locus and the nonproductively rearranged gene

39
Q

why can Cβ1 locus only be rescued by Cβ2?

A

DJ rearrangement ONLY occurs wihtin the respective Cβ locus

i.e. Dβ1 cannot rearrange with Jβ2

40
Q

where are the mouse TCR-α and TCR-δ genes located?

A

chromosome 14

41
Q

where are the α gene segments V, J, and C located relative to the δ gene segment?

A

at the two ends of the δ gene segment (V on left end and J, C on the right)

42
Q

what are the implications of the unusual location of Cδ between Vα and Jα?

A

results in the deletion of Cδ upon Vα-Jα rearrangement, meaning the cell looses its ability to create the TCR-δ chain

43
Q

how many Jα segments are there in the TCR-α chain gene?

A

~50

44
Q

what is permitted by the presence of many Jα segments?

A

TCR-α chain genes can undergo several successive rearrangement events to “leapfrog” over nonproductively rearranged VJα segments

45
Q

how long can the repeated rearrangements in the TCR-α gene continue?

A

until a productive rearrangement leads to positive selection
OR
until there are no more Vα or Jα segments available for rarrangement, leading to cell death

46
Q

if there is productive VJα rearrangement, will there ever be production of the δ chain? why or why not?

A

no never - it will be excised via DNA looping

47
Q

does TCR germ-line DNA contain fewer V gene segments than Ig germ-line DNA, or vice versa?
what are the implications of this?

A
  • TCR germ-line contains far fewer (i.e. there are more Ig variable genes than TCR)
  • can still make a large number of random combinations for all TCR chains just as IG heavy/light chains do
48
Q

how many V regions are present on the α, β, γ and δ chains?

A 
α = 100  
β = 25
γ = 7
δ = 10
49
Q

how many D regions are present on the α, β, γ and δ chains?

A 
α = 0  
β = 2
γ = 0
δ = 2
50
Q

how many J regions are present on the α, β, γ and δ chains?

A 
α = 50  
β = 12
γ = 3
δ = 2
51
Q

how many V regions are present on the Ig heavy and light chain?

A 
heavy = 300
light = 300
52
Q

how many D regions are present on the heavy and light chains?

A 
heavy = 12
light = 0
53
Q

how many J regions are present on the heavy and light chains?

A 
heavy = 4
light = 4
54
Q

explain how the alternative joining of D gene segments differs btwn TCR and Igs

A
  • due to the arrangement of RSS in TCR germ line DNA, alternative joining of D segments can occur
    (in the beta and delta chain ONLY)
  • also one D segment can join another (VDDJ) creating considerable diversity
  • this cannot occur in the Igs (they must obey the one-turn two-turn rule)
55
Q

explain how junctional flexibility differs btwn TCR and Igs

A
  • it doesnt - junctional flexibility is exhibited during gene rearrangement in both Igs and TCRs
  • it can generate many nonproductive rearrangements, but also increases diversity
56
Q

how does junctional flexibility increase diversity?

A

by encoding several alternative amino acids at each junction

57
Q

compare N-region nucleotide addition for Igs vs TCRs

A
  • in both Ig (heavy chain ONLY) and TCR genes, nucleotides may be added at the juncitons btwn some gene segments during rearrangement (as many as 6)
  • generates up to 5461 possible combinations assuming the random selection of nucleotides
58
Q

compare somatic mutations for TCR and Igs

A

no somatic mutations for TCR, but can have somatic mutations for Igs

59
Q

why are there no somatic mutations for TCR genes?

A

to ensure that T-cell specificity does not change after thymic selection (therefore reducing the possibilty that a random mutation may generate a self-reactive T-cell)

60
Q

who do somatic mutations occur for Igs?

A
  • largely random process - they occur in germinal centers where B-cells proliferate
  • these mutations target rearranged V regions located in the DNA sequence, influcencing the VJ and VDJ rearrangement processes
61
Q

compare allelic exclusion for TCRs vs Igs

A

Igs can and theres evidence to suggest that beta chain can and alpha chain can’t (no evidence for gamma or delta yet)

62
Q

T-cell receptors contain ____ that bind to the MHC-peptide complex

A

complementary-determining regions (CDR)

63
Q

how many CDRs do T-cell receptors contain? what are they

A

3! - CDR-1, CDR-2 and CDR-3

64
Q

where is CDR-1 located and what does it bind?

A
  • located in the variable region of the TCR

- interacts with the peptide in the MHC-peptide complex

65
Q

where is CDR-2 located and what does it bind?

A
  • located in the variable region of the TCR

- interacts with the alpha regions of the MHC in the MHC-peptide complex

66
Q

where is CDR-3 located and what does it bind?

A
  • located in the D-J region of the TCR

- interacts with the peptide in the MHC-peptide binding groove

micr 386 (31 decks)

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