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

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

Flashcards in Lecture 11 (6A) - Other T cell subsets Deck (58):
1

Peripheral tolerance
regulatory T cells (T-reg)

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

2

Regulatory T cells are able to

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

3

Naturally occurring CD4+ T-reg

CD4+
CD25+
Foxp3+

4

Inducible CD4+ T-reg

Tr1
TH3
and anergic

5

Other types of cells have regulatory activity

NKT cells
γδ T cells
CD8+ T-reg

6

Tolerance

to keep the immune system from attacking itself

7

Central tolerance

make T and B cells, then scan for autoreactive and kill
• detect, response, kill it and it's gone - final

8

Peripheral tolerance

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

9

Regulatory T cells actively and dominantly

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

10

Autoimmune disease

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

11

CD25

kills T-reg cells --> autoimmunity

12

Regulatory T cells were discovered by

Shimon Sakaguchi
• working on white mice

13

White mouse thymectomized at day 1 or 2

autoimmunity

14

White mouse thymectomized at day 4 or later

healthy mouse

15

Autoimmunity can be described as a balance between

regulatory T cells and effector T cells

16

In the white mouse T-regs are made

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)

17

CD4+ CD25+ cells are

naturally occurring regulatory T cells

18

Mouse without T cells or B cells

• 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

19

CD4+ CD25+
CD4+ CD25-

CD4+ CD25 + == regulatory
CD4+ CD25 - == effector

20

"Naturally occuring" regulatory T cells

• 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)

21

CD4+ CD25+ T-regs express

Foxp3 - the "master" gene for T-regs
• transcription factor

22

Foxp3 turns on many genes that

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

23

IPEX syndrome (stands for)

immune dysregulation, polyendocrinopathy, enterophthy, X-linked

• scurfy mouse naturally without Foxp3

24

IPEX syndrome

• 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