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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
Cells involved in suppressing and dampening down the immune response
Tregs
26
Tregs
- crucial for maintaining normal immunological **unresponsiveness** to self-antigens - suppress excessive immune responses that are damaging to the host
27
Foxp3 gene inactivating mutations
Tregs lose function spontaneous development of autoimmunity in mice *IPEX syndrome in humans
28
IBD and Tregs
Treg depletion can cause IBD from excessive immune response to commensal bacteria in the intestine
29
TFs that promote transcription of IL-2
- NFAT - AP1 - NFkB
30
IL-2 role in immune homeostasis | *7 points
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
Cyclosporin
dampens immune system by suppressing IL-2 production *inhibits calcineurin
32
Takrolimus
inhibits calcineurin - no NFAT produced - no IL-2 produced
33
CD25
IL-2 receptor alpha chain - highly expressed in Tregs - allows them to response to low conc. of IL-2
34
Tregs and IL-2
- 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
Main source of IL-2 for Tregs
**activated T cells** - activated Tregs then repress activity of activated CD4 T cells - negative feedback control of immune responses via IL-2
36
FoxP3
master regulatory of treg development and function
37
What are important for Foxp3 induction
TCR CD28 IL-2 autocrine Foxp3-dependent feedback loop
38
TFs that regulate Foxp3 expression
NFAT, AP1, STAT5, CREB | *bind to promoter region of Foxp3 *CNS1-3 also important
39
Where are FoxP3+ Tregs produced
thymus
40
periphery T regs
pTregs (intestinal mucousa) - important for acquisition of oral, mucousal, feto-maternal tolerance
41
What do FOxP3+ Tregs constitutively express
CD25 (IL-2 receptor) CTLA-4
42
Substance which promotes differentiation of thymocytes to tregs
TSLP | * Thymic stromal lymphopoietin
43
pTregs
develop from conventional CD4+ in periphery after antigen encounter due to influence of IL-2 and TGF-B
44
How do Tregs inhibit the immune system
-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
Peripheral tolerance
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
Tregs and tumour immunity
Tregs **hinder** anti-tumour immunity - cancers have tissue infiltrating FoxP3 - associated with poor prognosis (creates immunosuppressive environment)
47
Where to memory CD8 t cell descend from
effector CD8 T cells that have turned off their effector gene expression
48
3 main groups of memory T cells
1. Effector Memory T cells (TEMs) 2. Central Memory T cells (TCMs) 3. Tissue resident Memory T cells (TRMs)
49
TEMs
- 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
TCMs
- recirculate via secondary lympoid organs - increase with time after infection - Markers: CD62Lhi/CCR7hi - facilitates homing to SLOs
51
CD62L
L-selectin involved in adhesion
52
CCR7
homes cells to t cell zones in SLOs
53
TRMs
- **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
Cell surface markers for TRMs
CD103 - forms heterodimer receptor with B7 integrin for E-cadherin - allows TRMs to adhere to tissues for long time
55
CD69 and CXCR3
promotes tissue retention
56
CXCR3
binds to CXCL9 and CXCL10 - produced by inflammed tissue
57
CD8+ TRM & CD4 TRM
- mainly in BM of mucousal tissue and LNs
58
CD8+ TRM
important in detecting tumour development - can also kill virus infected cells

MB4030 (11 decks)

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