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Immunology and Infection > Development and Activation of T cells > Flashcards

Development and Activation of T cells Flashcards

1
Q

what do T cell receptors recognise?

A
  • internal epitopes buried within a pathogenic molecule

- only exposed when the pathogen infects a cell or taken up by an APC and processed and peptides made

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2
Q

how many TcRs does a T cell express?

A

up to 30, 000 TcRs

- these TcRs on a T cell will be specific for the same peptide

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3
Q

when do TcRs rearrange?

A

only rearrange during development in the thymus

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4
Q

what are the 2 types of T cell receptors?

A

alphaBeta TcR

gammaDelta TcR

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5
Q

what is the alphaBeta TcR?

A
  • predominant T cells circulating in your blood
  • found in the blood and secondary lymphoid tissues
  • role clearly defined
  • CD = helper
  • CD8 = killers
  • MHC restricted
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6
Q

what is the gammaDelta TcR?

A
  • minor population of T cells
  • found pre-dominantly in the epidermis and epithelia of reproductive and intestinal tract
  • role not clear
  • may not be MHC restricted
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7
Q

what is the structure of the alphaBeta TcR?

A
  • heterodimer
  • a chain linked to the aB chain
  • hyper variable region at the top
  • constant region below
  • have transmembrane regions and small cytoplasmic region
  • have a hinge just above the transmembrane region
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8
Q

what does the hinge region in the aB TcR provide?

A

gives the B cell flexibility

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9
Q

why is the aB TcR described as MHC restricted?

A

TcR must bind to both the MHC molecule and the peptide

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10
Q

how does the aB TcR align diagonally over the peptide MHC molecule?

A
  • TcR a chain lies over the a2 domain of MHC I and the amino terminal of the peptide
  • TcR B chain lies over the a1 domain of MHCI and COOH terminal of the peptide
  • HV regions of both TcR chains meet over the central amino acids of the peptide
  • trying to wrap itself around the whole of peptide-MHC complex and make contacts
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11
Q

why does the HV region of aB TcR have flexibility?

A
  • makes the TcR specific for one peptide, can reshape subtly to enable contact with another peptide
  • can twist and reform to form interactions
  • induced fit
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12
Q

how does the aB TcR heavy chain rearrange?

A

TcR B- heavy chain: V, D and J segments

- D recombines with J and then DJ with V

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13
Q

how does the aB TcR light chain rearrange?

A
  • TcR a - light chain: V and K segments

- V recombines with J

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14
Q

why is there a limited number of constant segments?

A
  • because the TcR solely acts as a receptor

- it is never secreted so it doesn’t need that many of them

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15
Q

what are the key points of TcR rearrangement?

A
  • RSS
  • 23/12 rule
  • make a hairpin loop to bring together the segments it wants to recombine
  • cut out the intervening sequences (TRECS)
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16
Q

what is the coding sequence?

A

coded to make the TcR you want

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17
Q

what is the role of Rag1 and Rag2?

A

facilitates the recombination process

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18
Q

what does the enzyme TdT do?

A

can add extra nucleotides to the free ends before the DNA ligase fixes everything
- gives junctional diversity

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19
Q

what does recombination require?

A

open DNA, TcR genes are in open chromatin

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20
Q

what is combinational diversity?

A
  • genetic recombination of a and B chain genes
  • mediated by RSS base pair repeats
  • mediated by the action of the recombinases RAG1 and RAG2
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21
Q

what could be a result of random rearrangement of TcR genes?

A

means some receptors form that are incapable of making contact with your own MHC molecules
- may be responsive to your own tissue molecules

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22
Q

what are the two key requirements of a TcR?

A
  • must be able to bind your own MHC otherwise you wont make an immune response to any infections
  • mustnt be able to recognise own peptides bound to MHC, you get autoimmunity
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23
Q

what is central tolerance?

A
  • removal of T cells with TcRs that can’t interact with host MHC or that binds host peptide
  • occurs in the thymus
  • results in T cells that have a receptor for specific non-self molecules
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24
Q

what is the thymus?

A
  • primary lymphoid organs
  • T cells develop and are educated
  • sits above the heart
  • bi-lobed
  • age driven atrophy (shrinks with age)
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25
Q

what are the features of T cell development in the thymus?

A
  • pluripotent HSCs transform to CLPs in bone marrow
  • CLPs enter the thymus
  • signals from thymus commit CLPs to T cell lineage
  • committed cells move to the cortex
  • only cells that pass negative and positive selection can circulate
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26
Q

what occurs when committed cells move to the cortex?

A
  • undergo positive selection
  • move to the medulla
  • undergo negative selection
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27
Q

what happens to the vast majority of developing T cells in the thymus?

A
  • most die

- 96-96% of all new thymocytes will die by apoptosis

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28
Q

what are the different stages of T cell development?

A
  • CIP
  • DN
  • DP
  • SP
  • Exit
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29
Q

what is meant by DN?

A
  • double negative

- CD4- and CD8-

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30
Q

what is meant by DP?

A
  • double positive

- CD4+ and CD4+

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31
Q

what is meant by SP?

A
  • single positive:
  • CD4- CD8+
  • CD4+ CD8-
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32
Q

which chain is rearranged first?

A

the heavy chain

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33
Q

what are the 4 cells that define the double negative stage?

A

DN1, DN2, DN3, DN4

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34
Q

what happens as cells move from DN2 to DN3?

A
  • signals in the stroma tell the CLP to start rearranging the segments of the TCR B chain
  • TcR B locus rearranges
  • goes to the cell surface for a checkpoint
  • checks that the B chain can complex with an a chain
  • makes a surrogate a chain called pTa
  • if it makes a stable interaction thats a positive signal into the cell
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35
Q

what happens in DN4?

A
  • stabilises the TCR B on the cell surfaces - tells the TcR a locus to start rearranging
  • triggers upregulation of CD4 and CD8
  • now in the double positive stage
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36
Q

what happens in DP?

A
  • TcR a rearranges and replaces the surrogate
  • get the complete TcR on the surface
  • ready for the first stage of central tolerance
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37
Q

what is positive selection?

A
  • cortex positively selets which developing T cells survive
  • important for educating T cells as to your MHC haplotype
  • developing DP cells interact with thymic cortical epithelial cells (CTECs)
  • CTECs express both MHC I and II and self peptides in the peptide binding cleft
  • strength of binding determines fate of developing T cell
38
Q

what will an unifencted cell carry on their MHCs?

A

your own peptide

39
Q

how does the strength of binding determines fate of developing T cell?

A
  • can it hook onto the MHC
  • a strong or moder association means the T cell will leave (need to attach for long enough for the T cell assess the peptide)
  • weak or no binding means the T cell will die
40
Q

what happens if the T cells has a stronger connection with MHC I?

A

will downregulate CD4 and become a CD8+ T cell

41
Q

what happens if the T cell has a stronger connection with MHC II?

A

will downregulate CD8 and become a CD4+ T cell

42
Q

what is the purpose of negative selection?

A

move to the medulla - removal of T cells that carry a receptor for a self-peptide

43
Q

what is the process of negative selection?

A
  • mTECs express both MHC and II with self-peptides in the peptide binding cleft
  • SP cells bind mTECs and depending on the signal strength they live or die
  • SP cells that survive leave the thymus and recirculate
44
Q

what does autoimmune regulated (AIRE) control?

A

Tissue Specific Antigen (TSA) expression

45
Q

what is the role of AIRE and TSA?

A
  • mTECs express AIRE resulting in expression of molecules from our peripheral tissue
  • forms peptides of important molecules for negative selection
  • high affinity interactions will lead to death of T cell bearing insule specific TCRs
46
Q

what does defects in AIRE production/activity lead to?

A

T cell mediated attack of our own tissues

47
Q

howcome you still get autoimmunity?

A

central tolerance of B and T cells is not absolute

48
Q

what has GWAS revealed?

A
  • a series of disease related to SNPs
  • DNA sequence variations occuring in the genome
  • strong allelic variants associated with autoimmunity are those with MHC
  • prevents effect negative selection as the MHC selects self-peptides that can only deliver a weak signal into the TcR
49
Q

what is a naive T cell?

A

has a TcR but hasnt encountered its antigen

50
Q

what is a primed T cell?

A

encountered the antigen for the first time and becomes activated

51
Q

what is an effector T cell?

A

fully activated and differentiated into a cell that damages the pathogen

52
Q

what is the immunological dilemma?

A
  • receptors on the surface of your cells that might react with your own cells
  • 5-10% actually autoreactive and circulate around the body
53
Q

how does the immune system prevent autoreactive T cells getting into the tissues?

A
  • restricted re-circulation of B and T cells and blood-ignorance of the immune system
  • a two signal pathway for activation of naive T cells
  • set threshold limits for T cell activation
  • special regulatory T cells
54
Q

what is the role of specialised regulatory T cell?

A

they seek out rogue immune cells that are attacking your own tissue and have the ability to suppress or kill them

55
Q

what is peripheral tolerance?

A

control of autoreactive cells outside the primary lymphoid organs

56
Q

what is restricted circulation?

A
  • stop a naive T cell from gaining entry to the tissues
  • bypasses in the bloodstream
  • if it can’t get out the bloodstream it wont recognise the tissue
  • restricts them in the bloodstream
  • need specialised extravasation
57
Q

how does the body prevent naive T cells getting to the site of infection?

A
  • extravasation occurs in lymph nodes and spleen but not peripheral tissues unless inflamed
  • governed by restricted expression of adhesion molecules and chemokines
  • adhesion molecules on naive T cells are different from those on activated T cells
  • will change its surface molecules
  • named peripheral tolerance
58
Q

what could be a problem if restricted recirculation fails eg leaky blood vessels?

A
  • every nucleated cells ahve MHC class I, if not infected self-peptide
  • APCs and host cells can present to self-peptides
59
Q

what do T cells need to be fully activated?

A

they require two signals

60
Q

what are the two signals required for T cell activation?

A
  • signal ONE; binding of the TcR to peptide MHC it recognises
  • signal TWO; binding of CD28 on T cells to costimulatory molecules CD80/CD86 on APCs
61
Q

what cells have the ability to provide the two signals to T cells?

A

antigen presenting cells

- your own tissues cant do this

62
Q

what if the T cell sees the MHC and the peptide and then is activated at another time and goes back and destroys it?

A
  • if it recieves one signal it becomes anergic

- stops it function permanently, completely unresponsiveness for its antigen

63
Q

other than APCs what else is needed to activate a CD8 T cell?

A

a CD4 T cell

64
Q

what can only APCs express?

A
  • costimulatory molecules CD80/CD86

- expression of these molecules on APC is controlled by inflammation

65
Q

what does inflammation upregulate?

A

upregulates the number of peptide MHC complexes and costimulatory molecules above the threshold for T cell activation

66
Q

what happens to T cells when there is no-infection?

A
  • cells die through natural processes
  • macrophages & DCs pick up fragments and load onto MHC
  • too few MHC peptide complexes and too few co-stimulatory molecules
  • APC controls number of complexes on surface based on whether there’s inflammation
67
Q

what happens to T cells when there is inflammation?

A
  • APC machinery is accelerated
  • more and more complexes
  • T cell recieves a very strong signal
  • inflammation increases production of MHC peptide complexes and costimulatory molecules
68
Q

what can dampening inflammation lead to?

A

more susceptibility to infection e.g. steroids

69
Q

why do T cells need a 3rd signal?

A

to induce differentiation into an effector: CD4 and CD8

70
Q

how are T cells activated?

A
  • APC and T cell come together
  • want to repel each other
  • MHC and TcR hook together
  • longer it binds the more powerful the signal
71
Q

what happens on initial contact between T cell and APC?

A
  • surface molecules are evenly distributed
  • if TcR binds there is a positive signal
  • there is a reorganisation of all the surface molecules to a central cap
72
Q

how is there reorganisation of all the surface molecules to a central cap?

A
  • reorganisation of the cytoskeleton
  • concentration of key molecules
  • called capping
  • initiates construction of a complex called the immunological synapse
73
Q

what is the role of capping?

A
  • creates the immunological synapse
  • brings together molecules that initiate TcR signalling
  • can’t get T cell activation without the immunological synapse
  • exclude CD43 and CD45
  • Ig and integrins
74
Q

why are CD43 and CD45 excluded in capping?

A

their job is to prevent synapse formation so get pushed away

75
Q

what is the role of Ig and integrins?

A
  • have a role to make the adherence of the APC and the T cell really tight
  • Ig such as ICAM-1
  • integrins such as LAF1
76
Q

what are the properties of the TcR?

A
  • no capacity to signal
  • co-expressed alongside the CD3 complex
  • CD3 complex has 4 subunits
  • CD3 complex tranmsits signal from TcR into the cell
77
Q

what does TcR bind?

A

binds MHC and there is a conformational change

- activates CD3 complex which phosphorylates molecules

78
Q

what is the role of CD3?

A
  • Formation of immunological synapse recruits kinases to CD3
  • CD3 complex contains immunoreceptor tyrosine based activational motifs (ITAMs)
  • ITAMs phosphorylation by kinases triggers a biochemical cascade
  • Phosphorylation of CD28 amplifies the TCR signal
  • CD3  chain transmits signals via the TCR by recruitment of kinase Zap-70
79
Q

what is the role of CD4 (or CD8)?

A
  • CD4 (or CD8) acts as a co-receptor and recruits kinase LcK

* LcK triggers phosphoinositol kinase (PI3K) activity leading to cell proliferation and survival

80
Q

what is the sum of all the TcR activations?

A

to induce IL-2

81
Q

what is interleukin?

A

growth and survival cytokine for T cells

- cant have an effective immune response without it

82
Q

why is interleukin so important in the activation of naive T cells?

A
  • naive T cell have low affinity IL-2 receptor

- TcR triggered small amount of IL-2 is produced

83
Q

what effect does IL-2 have on the TcR?

A
  • triggers upregulated production of the high affinity receptor
  • alpha is high affinity
  • this means all the T cells in the vicinity suck up IL-2
  • results in massive proliferation of T cells
  • this is clonal expansion
84
Q

why do CD8 T cells need CD4 T cell help?

A
  • CD8+ T cells cant produce sufficient quantities of IL-2
  • need CD4 T cell help
  • without IL-2 the CD8+ T cells will die
  • two signal activation also occurs during central tolerance
85
Q

why do activated T cells need to be switched off?

A

to prevent damage to the host

86
Q

how does switching off occur?

A

occurs following signalling through negative co-stimulatory molecules

87
Q

what are the key molecules involved switching off activated T cells?

A
  1. cytotoxic lymphocyte antigen (CTLA)-4

2. programmed death domain (PD)-1

88
Q

what is CTLA-4?

A
  • CD28 binds to CD80/CD86  kinases and amplification of positive signals
  • Cytoplasmic tail of CDTLA-4 has an immunoreceptor tyrosine based inhibitory motif (ITIM)
89
Q

what is ITIM?

A
  • Recruits phosphatases to the receptor complex

- This de-phosphorylates key molecules in T cell activation

90
Q

what is PD-1?

A
  • PDL-2 on APC
  • PDL-1 on peripheral tissue  switch T cells off that have got into our tissue
  • PD1 has a cytoplasmic ITIM and dephosphorylates key molecules
  • Mutations of CTLA-4 or PD-1 results in an autoimmune attack on our own tissues

Immunology and Infection (13 decks)

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