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MB4030 > L5: T Cells > Flashcards

L5: T Cells Flashcards

1
Q

How do Th cells and CTLs ‘see’ antigens?

A

Through their TCR (very polymorphic)

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2
Q

A T cell receptor is non-covalently associated with how many other proteins?

A

5 other proteins, to form a CD3 protein complex

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3
Q

What is CD3 involved in?

A

Signal transduction following recognition of its antigen

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4
Q

What are the components of the ‘tri-molecular complex’

A

TCR, antigen, MHC

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5
Q

Viral proteins are degraded to peptides and loaded onto which MHC class molecules?

A

Class I
(this alerts the immune system of infection)

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6
Q

APCs load short peptide antigens from the killed pathogen onto which MHC class molecules?

A

Class II
(they are then presented to TCR on Th cells)

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7
Q

MHC Class I antigens are typically recognised by which T cells?

A

CD8+ cytotoxic T cells (CTLs)

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8
Q

MHC Class II antigens are typically recognised by which T cells?

A

CD4+ T helper cells

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9
Q

Where do immature thymocytes mature into Th cells and CTLs?

A

the thymus

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10
Q

Why is the maintenance of immune response to ‘self’ in the thymus essential?

A

to prevent untoward immune responses and autoimmunity

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11
Q

What is the purpose of thymic education of thymocytes to naive T cells?

A

to eliminate any T cells that could potentially attack our own cells/tissues i.e. self-antigens

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12
Q

What are the 4 main cell types involved in the process of antigen presentation to maturing thymocytes?

A

Interdigitating dendritic cells
Thymic medullary epithelial cells (mTECs)
Cortical epithelial cells
Macrophages

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13
Q

Thymocytes are derived from…

A

lymphoid stem cells

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14
Q

99% of mature thymocytes have…

A

an αβTCR, the remainder have a 𝛾𝛿TCR

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15
Q

Where are 𝛾𝛿TCRs mainly found?

A

in the gut mucosa

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16
Q

Briefly explain the thymocyte maturation stages

A
  1. βTCR chain rearranges, CD3 in cytoplasm
  2. ~80% of thymocytes at any one time (double positives), CD1+ (homing marker), CD4+ CD8+ co-expression, αTCR chain rearranges, low density surface expression
  3. thymic education takes place, mature thymocytes are now CD1- and either CD4+ or CD8+ (single positives), high density surface expression of αβTCR
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17
Q

What happens in positive selection?

A

‘Dual recognition’ of (i) functional TCR (on T cell surface) and (ii) ability to recognise MHC molecules on the surface of an APC

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18
Q

What happens in negative selection?

A

The deletion of ‘self-reacting’ T cells
(if a TCR is autoreactive, it is killed by APCs via apoptosis and the apoptotic bodies are removed by macrophages)

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19
Q

What does the chemokine CCL25 do?

A

attracts progenitors to the thymus

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20
Q

How do thymic nurse cells support thymocyte proliferation?

A

by producing IL-7

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21
Q

What happens when single positive thymocytes leave the thymus?

A

They become naive effector T cells (Teff cells)

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22
Q

What is Aire?

A

a transcription factor that is highly expressed in mTECs and promotes the expression of 1000s of TSAs

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23
Q

What happens when developing thymocytes interact with TSAs?

A

negative selection of these thymocytes

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24
Q

True or False: Each mTEC will randomly express a given TSA gene.

A

True

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25
Q

Aire-induced TSAs in mTECs are expressed as orders of magnitude lower or higher than their expression in peripheral tissues?

A

Lower (you don’t want a large amount of these proteins made in mTECs)

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26
Q

Studies suggest that the capacity of Aire to regulate expression of a huge array of TSAs relies solely on…

A

unconventional transcriptional mechanisms, without intermediary transcription factors

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27
Q

Many additional proteins have been identified that assist Aire to recognise target TSAs by…

A

releasing stalled RNA polymerase to allow RNA elongation
(these proteins also regulate Aire itself)

28
Q

What is the repressive epigenetic marker that is recognised by Aire?

A

unmethylated histone 3 lysine 4 (H3K4)

29
Q

How does Aire appear different to other transcription factors?

A

Aire does not have a clear DNA binding motif but instead recognises genes that possess silenced/repressed chromatin states

30
Q

What happens to the thymus after 40 years of age?

A

begins to involute and turn to fatty tissue, greatly reduces in size

31
Q

What is the loss of thymic TECs associated with?

A

thymic atrophy and reductions in thymopoiesis

32
Q

The expression of which TF in TECs decreases with age?

A

FoxN1
(causing rapid depletion of TECs)

33
Q

What thymocyte-promoting factors are reduced in TECs with age?

A

IL-7 and MHCII

34
Q

Does thymic involution occur faster in males or females?

A

Males
(role for androgens in thymic atrophy?)

35
Q

What are Tregs essential for?

A

the maintenance of immunological self-tolerance and homeostasis

36
Q

What does a thymectomy lead to?

A

inflammation and severe organ-specific autoimmune pathogenesis

37
Q

What do loss-of-function mutations in the FoxP3 gene cause?

A

IPEX syndrome in humans
(spontaneous development of severe autoimmunity in mice)

38
Q

What transcription factors promote IL-2 transcription?

A

NFAT, NF-κβ, AP-1

39
Q

What are the roles of IL-2?

A
  1. stimulates production of other cytokines by T cells & APCs
  2. promotes B cell maturation
  3. promotes CTL/NK cell killing
  4. crucial for growth & maintenance of FoxP3 Tregs, and stable FoxP3 expression
  5. CD4+ and CD8+ cell proliferation and growth
  6. promotes apoptosis in antigen-activated T cells at the end of an infection
  7. optimal development, survival and function of Tregs
40
Q

What are Tregs positive for?

A

CD4, CD25, FoxP3

41
Q

Tregs are essential for?

A

(i) Limiting the activity of Teffs during proinflammatory responses
(ii) Maintaining self-tolerance

42
Q

What allows Tregs to respond to very low concentrations of IL-2?

A

IL-2 receptor alpha chain (CD25) is highly expressed in Tregs

43
Q

What gene does FoxP3 in Tregs repress, and what is the result of this?

A

IL-2 gene
As a result, Tregs scarcely produce any IL-2 and are highly dependent on exogenous IL-2 for their survival

44
Q

Activated Tregs repress the activity of?

A

activated CD4+ T cells

45
Q

FoxP3 is a master regulator of?

A

Treg development and function

46
Q

What are important for induction of FoxP3?

A

TCR and CD28 costimulatory signals, as well as IL-2 and an autocrine FoxP3-dependent feedback loop

47
Q

How is FoxP3 expression regulated?

A

By several transcription factors: NFAT, AP-1, STAT5, CREB binding to the promoter region of the FoxP3 gene
As well as 3 highly conserved non-coding sequences (CNS1-3) in the genomic FoxP3 region

48
Q

Tregs account for __% of T cells

A

~5-15%

49
Q

What produces the majority of FoxP3+ Tregs in the immune system?

A

the thymus
(generated as a separate lineage at the stage of CD4+ SP thymocytes)

50
Q

Some T cells differentiate into Tregs in…

A

the periphery, especially in the intestinal mucosa

51
Q

pTregs develop from conventional CD4+ in the periphery after antigen encounter or…

A

due to the influence of IL-2 and TGFβ

52
Q

FoxP3 Tregs constitutively express __ and __ on the cell surface at high levels.

A

CD25 (high affinity IL-2 receptor) and CTLA-4

53
Q

How do Tregs inhibit the immune system?

A
  • Secretion of inhibitory cytokines (IL-10, TGFβ, IL-35) and intracellular molecules (Granzyme, cAMP, IDO)
  • Cell-contact inhibition mechanisms involving specific cell surface receptors: CTLA-4, CD25, CD39
  • Peripheral tolerance (inhibition of any self-reactive CD4 or CD8 cells that might have escaped thymic education)
54
Q

High levels of Tregs in cancer patients are often associated with?

A

poor prognosis because they create an immunosuppressive environment

55
Q

Name the 3 main groups of memory T cells

A
  1. Effector memory T cells (Tem)
  2. Central memory T cells (Tcm)
  3. Tissue-resident memory T cells (Trm)
56
Q

Role of effector memory T cells

A
  • recirculate between blood and non-lymphoid tissues
  • provide a rapid response to reinfection
  • carry out cytotoxic functions and secrete effector cytokines upon antigen reencounter
57
Q

Effector memory T cell markers?

A

CD62Llo/CCR7lo
however, they express integrins and chemokine receptors required for localisation in inflamed/infected tissues

58
Q

Role of central memory T cells

A

recirculate via secondary lymphoid organs (increase with time after infection)

59
Q

Central memory T cell markers?

A

CD62Lhi/CCR7hi
(CD62L is an L-selectin involved in adhesion, CCR7 homes the cells to the T cell zones in SLOs)

60
Q

Role of tissue-resident memory T cells

A
  • Provide enhanced localised immunosurveillance and protect the peripheral tissues such as skin, lungs, brain, liver, bladder, GIT
  • Rapidly activated to fight infection
61
Q

What is different about tissue-resident memory T cells?

A

They do not circulate

62
Q

Which two molecules form a heterodimer receptor for E-cadherin?

A

CD103 and integrin β7

63
Q

What allows Trm cells to adhere to tissue for a long time?

A

Integrin CD103 (αE-type integrin), LFA-1 & VLA-1

64
Q

Which cell surface markers promote tissue retention?

A

CD69 and CXCR3

65
Q

CXCR3 binds?

A

CXCL9 and CXCL10, produced by inflamed tissue

66
Q

Where do CD4 and CD8 Trm cells mainly settle?

A

in the basement membrane of mucosal tissue and in the lymph nodes

67
Q

What are CD8+ Trm cells important for?

A

detecting tumour development, can also kill virus-infected cells

MB4030 (10 decks)

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