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MB4030 > T cells > Flashcards

T cells Flashcards

1
Q

Where do thymocytes mature

A

Thymus

  • thymocytes mature into Th & CTLs
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2
Q

Thymic education

A

thymocytes to naive T cells
- eliminated T cells that could potentially attack our own cells/tissues aka self-antigens

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3
Q

Cells involved in antigen presentation to maturing thymocytes

A
  • IDCs
  • Thymic medullary epi cells (mTECs)
  • cortical epi cells
  • macrophages
  • cells present self antigens to thymocytes - forbidden food - if thymocytes bite -> killed via apoptosis
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4
Q

Where are thymocytes derived from

A

Lymphoid stem cells
- mature cells
- +/- selected in cortex/medulla
- 99% have αβTCR
- remainder have γδTCR

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5
Q

Maturation stages of thymocytes

A

Stage I
- βTCR chain rearranges (CD3 in cytoplasm)
- double -ve
(CD4-, CD8-)

Stage II
- 80% of thymocytes
- Double +
(CD1+, CD4+, CD8+)
- alpha chain rearranges
- low density surface expression

Stage III
- matured thymocytes
(CD1-)
- single +
(CD4+ or CD8+)
- high density surface expression of αβTCR on cell

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6
Q

CD1 function

A

Keeps thymocytes in thymus

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7
Q

positive selection

A

tests for dual recognition of
- functional TCR on T cell surface
- recognises MHC molecules on APC surface

*has both T cell and TCR made -> can interact with MHC

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8
Q

negative selection

A

deletion of self-reacting T cells/thymocytes
- if TCR recognises self antigens -> thymocyte killed by APCs (apoptosis)
- apoptotic bodies removed by phagocytes (mainly macrophages)

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9
Q

thymic nurse cell

A

supports thymocyte proliferation by producing IL-7

*haemopoietic growth factor

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10
Q

Single positive thymocyte fate

A

Leave thymus and become naive effector T cells (Teff)

*both CD8 and CD4

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11
Q

How many thymocytes make it through education process

A

Only 1-2%

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12
Q

Where is AIRE expressed

A

mTecs

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13
Q

How can small set of APCs in thymus present ALL self antigens expressed in the body?

A

Aire (TF expressed in thymic medullary epi cells)
- promotes expression of 1000s TSAs

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14
Q

mTECs

A
  • each mTEC express a TSA gene
  • co-expression of other genes
  • genes clustered at a particular location on chromosome
    -> increased chromatin accessibility

*broad range of self TSAs being displayed to T cells by diverse pool of mTECs

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15
Q

mTEC expression in peripheral tissues

A

magnitude lower

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16
Q

Additional proteins that assist AIRE

A

**release stalled RNA polymerase **

  • allow RNA elongation
  • regulates AIRE itself
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17
Q

Gene silencing

A

induced by the repressed chromatin structure
- marked by the loss of methylation at histone H3 lysine 4 (hypomethlation)

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18
Q

H3K4

A
  • unmethylated H3 lysine 4
  • repressive epigenetic marker
  • recognised by AIRE
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19
Q

How is AIRE different to other TFs?

A
  • **no clear **DNA binding motif
  • recognises genes that possess silenced/repressed chromatin states
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20
Q

Aging and thymus

A
  • largest at birth
  • most active up until puberty
  • after this point it begins to involute and turn to fatty tissue
  • active thymic tissue with DP thymocytes reduces after age 40
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21
Q

Thymic atrophy

A

associated with the loss of thymic TECs -> thymopoiesis

*process by which thymocytes turn into mature T cells

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22
Q

Factors that are reduced with age in TECs

A
  • IL-7
  • MHC II
  • FoxN1

*thymocyte promoting factors

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23
Q

FoxN1

A

expression of this TF in TECs decrease with age
-> causes rapid depletion of TECs

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24
Q

Is thymic involution faster in males or females

A

males
- role of androgens perhaps in thymic atrophy?

25
Q

Cells involved in suppressing and dampening down the immune response

A

Tregs

26
Q

Tregs

A
  • crucial for maintaining normal immunological unresponsiveness to self-antigens
  • suppress excessive immune responses that are damaging to the host
27
Q

Foxp3 gene inactivating mutations

A

Tregs lose function
spontaneous development of autoimmunity in mice

*IPEX syndrome in humans

28
Q

IBD and Tregs

A

Treg depletion can cause IBD from excessive immune response to commensal bacteria in the intestine

29
Q

TFs that promote transcription of IL-2

A
  • NFAT
  • AP1
  • NFkB
30
Q

IL-2 role in immune homeostasis

*7 points

A

IL-2
1. stimulates production of other cytokines by T cells and APCs, promotes **B cell maturation, CTL/NK cell killing
2. crucial for growth and maintenance of Foxp3 Tregs
3. IL-2 expression requires activation of a variety of TFs
4. crucial for CD4+, CD8+ proliferation and growth
5. promotes apoptosis in antigen-activated T cells (dampens down**)
6. essential for development, survival and function of Tregs
7. maintains Foxp3+ natural Tregs and expands them

31
Q

Cyclosporin

A

dampens immune system by suppressing IL-2 production
*inhibits calcineurin

32
Q

Takrolimus

A

inhibits calcineurin
- no NFAT produced
- no IL-2 produced

33
Q

CD25

A

IL-2 receptor alpha chain
- highly expressed in Tregs
- allows them to response to low conc. of IL-2

34
Q

Tregs and IL-2

A
  • Foxp3 represses IL2 gene
  • Tregs scarcely produce any IL2 - dependant on exogneous IL2 for survival
  • tregs able to absorb most of IL2 due to large numbers of high affinity IL2 receptors (CD25)
35
Q

Main source of IL-2 for Tregs

A

activated T cells
- activated Tregs then repress activity of activated CD4 T cells
- negative feedback control of immune responses via IL-2

36
Q

FoxP3

A

master regulatory of treg development and function

37
Q

What are important for Foxp3 induction

A

TCR
CD28
IL-2
autocrine Foxp3-dependent feedback loop

38
Q

TFs that regulate Foxp3 expression

A

NFAT, AP1, STAT5, CREB

*bind to promoter region of Foxp3
*CNS1-3 also important

39
Q

Where are FoxP3+ Tregs produced

A

thymus

40
Q

periphery T regs

A

pTregs
(intestinal mucousa)
- important for acquisition of oral, mucousal, feto-maternal tolerance

41
Q

What do FOxP3+ Tregs constitutively express

A

CD25 (IL-2 receptor)
CTLA-4

42
Q

Substance which promotes differentiation of thymocytes to tregs

A

TSLP

* Thymic stromal lymphopoietin

43
Q

pTregs

A

develop from conventional CD4+ in periphery after antigen encounter due to influence of IL-2 and TGF-B

44
Q

How do Tregs inhibit the immune system

A

-secretion of inhibitory cytokines (IL-10, TGF-B, IL-35)
- secretion of intracellular molecules (granzyme, cAMP, IDO)
- cell contact inhibition involving cell surface receptors (CTLA-4, CD25, CD39)

45
Q

Peripheral tolerance

A

protect body from unwanted and harmful immune reponses towards self-antigens
- activates highly sensitive Tregs (dominant self-tolerance to self-antigens released from damaged tissues)

*ensures inhibition of selfreactive CD4 CD8 (may have escaped during TE)

46
Q

Tregs and tumour immunity

A

Tregs hinder anti-tumour immunity
- cancers have tissue infiltrating FoxP3
- associated with poor prognosis (creates immunosuppressive environment)

47
Q

Where to memory CD8 t cell descend from

A

effector CD8 T cells that have turned off their effector gene expression

48
Q

3 main groups of memory T cells

A
  1. Effector Memory T cells (TEMs)
  2. Central Memory T cells (TCMs)
  3. Tissue resident Memory T cells (TRMs)
49
Q

TEMs

A
  • recirculate between blood and non-lymphoud tissues
  • rapid response to reinfection
  • survive for long time
  • cytotoxic functions (secrete effector cytokines upton Ag re-encounter)
  • Markers: CD62Llo/CCR7lo
  • express integrins and chemokine receptors required for localisation in inflammed tissue
50
Q

TCMs

A
  • recirculate via secondary lympoid organs
  • increase with time after infection
  • Markers: CD62Lhi/CCR7hi
  • facilitates homing to SLOs
51
Q

CD62L

A

L-selectin involved in adhesion

52
Q

CCR7

A

homes cells to t cell zones in SLOs

53
Q

TRMs

A
  • **do not circulate
  • permanent tissue residents**
  • provide enhanced localized immunosurveillance
  • protect peripheral tissues
  • rapidly activated to fight infection
  • found in immune-priviledges areas of brain
  • observed in chronically batcerial infected intestinal mucosa/bronchi of lungs
54
Q

Cell surface markers for TRMs

A

CD103
- forms heterodimer receptor with B7 integrin for E-cadherin
- allows TRMs to adhere to tissues for long time

55
Q

CD69 and CXCR3

A

promotes tissue retention

56
Q

CXCR3

A

binds to CXCL9 and CXCL10
- produced by inflammed tissue

57
Q

CD8+ TRM & CD4 TRM

A
  • mainly in BM of mucousal tissue and LNs
58
Q

CD8+ TRM

A

important in detecting tumour development
- can also kill virus infected cells

MB4030 (11 decks)

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