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Basic Immunology > Lecture 11 (6A) - Other T cell subsets > Flashcards

Lecture 11 (6A) - Other T cell subsets Flashcards

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1
Q

Peripheral tolerance

regulatory T cells (T-reg)

A

regulatory T cells are able to prevent other T cells from generating an immune response to a particular antigen

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2
Q

Regulatory T cells are able to

A

prevent other T cells from generating an immune response to a particular antigen

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3
Q

Naturally occurring CD4+ T-reg

A

CD4+
CD25+
Foxp3+

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4
Q

Inducible CD4+ T-reg

A

Tr1
TH3
and anergic

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5
Q

Other types of cells have regulatory activity

A

NKT cells
γδ T cells
CD8+ T-reg

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6
Q

Tolerance

A

to keep the immune system from attacking itself

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7
Q

Central tolerance

A

make T and B cells, then scan for autoreactive and kill

• detect, response, kill it and it’s gone - final

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8
Q

Peripheral tolerance

A

few self reactive escape into body - regulatory T cells kill them
• may suppress response through life

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9
Q

Regulatory T cells actively and dominantly

A

suppress self-reactive T cells that exist in the normal periphery

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10
Q

Autoimmune disease

A

may develop as a consequence of altered balance between T-reg cells and self-reactive effector T cells

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11
Q

CD25

A

kills T-reg cells –> autoimmunity

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12
Q

Regulatory T cells were discovered by

A

Shimon Sakaguchi

• working on white mice

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13
Q

White mouse thymectomized at day 1 or 2

A

autoimmunity

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14
Q

White mouse thymectomized at day 4 or later

A

healthy mouse

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15
Q

Autoimmunity can be described as a balance between

A

regulatory T cells and effector T cells

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16
Q

In the white mouse T-regs are made

A

after day 4
• at birth lots of DN and DP but few actual CD4 cells
• at birth CD4 start to be produced, some are self-reactive
• this means they need regulatory T cells to ensure they don’t get autoimmunity
• T reg not made until day 4
• remove thymus before day 4 = make some self-reactive but no T-reg
• after day 4 some self-reactive but also some police cells (T-reg)

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17
Q

CD4+ CD25+ cells are

A

naturally occurring regulatory T cells

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18
Q

Mouse without T cells or B cells

A

• purified cells from a normal mouse
• gave the SCID mouse only CD4+ CD25- cells (effector)
–> gastritis (autoimmune disease)
-of course there were some autoreactive T cells in the mix but no regulatory T cells to protect them
• gave the SCID mouse CD4+ CD25- (effector) and
CD4+ CD25+ (reguatory) cells
–> no gastritis

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19
Q

CD4+ CD25+

CD4+ CD25-

A

CD4+ CD25 + == regulatory

CD4+ CD25 - == effector

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20
Q

“Naturally occuring” regulatory T cells

A
  • CD4+ CD25+ T-regs
  • have a TCRαβ that is thought to recognize self-antigens
  • express a gene called Foxp3 (master gene for T-regs)
  • Foxp3 turns on many genes that turn T cells into regulatory T cells (CRLA-4, GITR, CD25)
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21
Q

CD4+ CD25+ T-regs express

A

Foxp3 - the “master” gene for T-regs

• transcription factor

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22
Q

Foxp3 turns on many genes that

A

turn T cells into regulatory T cells
• CTLA-4
• GITR
• CD25

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23
Q

IPEX syndrome (stands for)

A

immune dysregulation, polyendocrinopathy, enterophthy, X-linked

• scurfy mouse naturally without Foxp3

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24
Q

IPEX syndrome

Study These Flashcards
A 
• human gut syndrome resulting in a mutation in Foxp3
• no Foxp3 = no T-reg 
• autoimmune disease strikes soon after birth
• x-linked - so mostly affects boys
• 90% of patients develop diabetes
(T cells attack pancreas)
• ~70% develop thyroiditis
• high mortality rate
25
Naturally occurring T-regs develop in
the thymus
26
Naturally occurring nT-regs | affinity
• no recognition of self-antigens = low affinity --> death • moderate recognition of self antigens = medium affinity -- weaker 2/3 --> positive selection (CD4+ T cells) -- stronger 1/3 --> selection (CD4+ nT-reg cells) • perfect recognition of self-antigens = high affinity -- weaker 1/3 --> selection (CD4+ nT-reg cells) -- stronger 2/3 --> negative selection APPEAR TO RESPOND TO SELF ANTIGEN • autoimmunity if causes inflammation and releases lots of cytokines • recognizes self antigens and make cytokines that dampen immune response ***** - don't make inflammatory responses (high medium affinity and low high affinity)
27
Foxp3+ T-regs also come from
CD4+ T cells in the periphery
28
Inducible iT-regs develop in
the periphery - particularly in the gut CD4+ Th0 cell --> CD4+ iT-reg cell • induced by TGFβ and retinoic acid (abundant in gut) • inhibited by IL6/IL21
29
nT-regs vs iT-regs
nT-regs (naturally-occurring) • made in thymus • transcription factor Foxp3 • protect from autoimmunity iT-regs (inducible) • develop in the periphery - esp the gut • induced by TGFβ and retinoic acid (abundant in gut) • protect from responses to environment you shouldn't be making (eg allergies to food)
30
IL6/IL21
very pro-inflammatory • IL6 made by damaged tissue • inhibits iT-reg cell
31
Lots of TGFβ and retinoic acid
in the gut • induce CD4+ Th0 cells to become iT-reg * in the gut we have lots of proteins we don't want to make a response to * allow us to have regulation against environment when induced
32
CD4+ iT reg
* develop in the periphery (esp the gut) * from CD4+ Th0 form CD4+ iT-reg if induced by TGFβ and retinoic acid (abundant in gut) * inhibited by IL6/IL21 * make TGFβ and other suppressive molecules (with help of Foxp3)
33
How do nT-reg cells work
eg in the lymph node • DC presenting MHC-II + self antigen - presenting self-antigen = don't want effector response • the effector (CD4+) T cell may be stimulated by it and make IL2, divide • regulatory T cell also recognizes self-antigen, comes in -- like self-antigens that give signals --LOVE IL2 • in the presence of IL2 the Treg regulates, dampens the response • the T-reg can turn off the DC or the T cell directly
34
Ways the nT-reg cell inhibits the DC or CD4+ effector cell
Cell-cell contact • CD39 • CD73 • LAG-3 Possible role for • CTLA4 ** • GITR Possible role for • granzymes/perforin Soluble factors • IL-10 • IL-35 • Galectin-1
35
CTLA4
* expressed by Treg * without it = autoimmunity * similar to CD28 in that it binds B7 * B7 is on DC, needed for T cell responses to start * CTLA4 costimulatory when binds B7 - but most of it is inside the T-reg (95%) * the turnover onto the surface is massive - always cycling onto the surface then going back inside the Treg cell * while on the surface, comes in while grabbing B7 off the DC and taking it into the cell * the DC then has no B7 so can't activate naive T cells any more
36
Inducible regulatory T cells
* Tr1 cells | * TH3 cells
37
Tr1 Cells make
* IL-10 | * TGFβ
38
TH3 Cells make
TGFβ
39
Conditions that generate Tr1 cells
• T cell priming in the presence of immature dendritic cells (APC that lack full costimulatory activity) • T cell priming in the presence of IL-10 • T cell priming in the presence of vitamin D3 analogues or steroids THEY DO NOT EXPRESS FOXP3
40
Tr1 cells don't
DO NOT EXPRESS FOXP3
41
Generation of an effector T cell
fully activated APC ``` signal 1 = MHC + antigen to TCR signal 2 = costimulatory • CD40 on APC + CD40L on T cell • B7.1 and B7.2 on APC + CD28 on T cell signal 3 = IL-2 - signal to divide repeatedly ```
42
Generation of a Tr1 T cell
partially activated APC signal 1 = MHC + antigen to tCR signal 2 = costimulatory molecules (low) • T cell has CD40L but APC has low CD40 • T cell has CD28 but APC has low B7.1 and B7.2 • sometimes would switch off, but if vitamin D3 and steroids get Tr1 cell (from dead cell so don't want immune response because have live cells with those proteins) APC releases cytokines IL-10, vitamin D3, steroids (necessary)
43
Mode of action of Tr1 cells
makes IL-10 and TGFβ • broadly immunosuppressive cytokines • inhibit IL-2 secretion = block T cell proliferation • inhibit cytokine secretion by effector cells (Th1 or Th2 cells) • inhibit APC function - downregulate MHC-II and costimulatory molecules
44
Induced Tr1 cells
dendritic cell in lymph nodes displays MHC-II + peptide • CD4+ CD25- effector T cell recognizes peptide • Tr1 cell inhibits effector response by recognizing the same antigen, then produces IL-10 and TGFβ
45
Regulatory T cells - TH3 cells
* secrete high levels of TGFβ * secrete little/no IL-10 * induced following oral tolerance induction * suppress T cell proliferation/cytokine production
46
TH3 cells oral administration of autoantigens
feed food to cells, and they make Foxp3 and a population of cells without Foxp3 but make lots of TGFβ • make mice resistant to induction of autoimmune disease by feeding them antigen • mash up protein, feed that antigen to the mouse in food • if you then try to induce autoimmunity by immunizing, can't be done because made regulatory cells in gut --> can't then induce selfreactive response
47
A healthy individual
effector T cells and regulatory T cells are balanced
48
Infection
effector T cells are more than regulatory T cells --> resolution of infection
49
In the absence of infection
make more effector T cells than regulatory T cells | --> autoimmunity
50
cancer
make more regulatory T cells than effector T cells - -> poor prognosis - stops immune cells from killing tumours
51
NKT cells
• are T cells - have αβ TCR • often have an invariant TCR (all have similar TCR) • they have many features of NK cells • they recognize glycolipids presented by CD1 (CD1 looks like MHC-I, not proteins) • numbers of NKT cells vary substantially between people
52
Subsets of NKT cells
* Type I NKT cells (CD1d restricted) * Type II NKT cells (Cd1d-restricted) * other NKT cells (CD1a, b, c restricted - human) all recognize lipids (esp glycolipid) - not proteins
53
Positive selection is on
DP cells in the thymic cortex | by cortical epithelial cells
54
Negative selection is on
mature T cells in the thymic medulla | by thymic dendritic cells and medullary epithelial cells
55
NKT cells are made in
the thymus
56
NKT cells are derived from
DP cells selected on CD1/lipids presented by other DP cells
57
NKT cells are derived from DP cells | selected on CD1/lipids presented by other DP cells
DP cell going to become NKT has NKT receptor that recognizes lipid + CD1 • DP cells don't use epithelial cells to present peptides (like how it's checked for self-reactivity) • NKT cells look at other DP cells • if it sees another DP cell with CD1 and lipids being presented, there's a DP-DP interaction • if the DP-DP occurs, there's a SLAM:SLAM interaction • signals to the receiving cell to become NKT
58
What is the function of NKT cells
• receives IL-25 • then releases cytokines • function is tissue-dependent • function is rapid - in tissues - no priming required • function can be pro-inflammatory or regulatory, and is cytokine-driven • NKT cells are implicated in/modulate many disease states - autoimmunity - cancer - infection - transplant rejection

Basic Immunology (15 decks)

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