lecture 5 Flashcards

1
Q

what is the method of T cell mediated immunity?

A
  1. naive T cells (that have survived +ve and -ve selection) leave the thymus
  2. recirculate via blood/lymphatics through secondary lymphoid tissue
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2
Q

what do naive T cells express?

A

either CD4 or CD8

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3
Q

how do naive T cells become effector/memory T cells?

A

when encounter an antigen

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4
Q

what does contact with a specific antigen and APC lead to?

A

clonal proliferation and differentiation

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5
Q

what do cd8 T cells do?

A

kill infected cells
cytotoxic effect

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6
Q

what do cd4 T cells do?

A

secrete cytokines
helper effector T cells

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7
Q

what happens in the lymphoid tissue?

A
  1. T cells recognise Ag/MHC on APCs
  2. array of APC found, trap and present Ag (in lymph nodes or spleen where T cells go once leave thymus)
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8
Q

what happens following activation of T cells?

A
  • T cell effects leave the areas and migrate to the sites of infection
    -deals with the start site of pathogen entry
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9
Q

how do naive T cells get where they need to be?

A
  1. enter lymph node from blood via high endothelial venules (HEV)
  2. move into T cell area that is rich in dendritic cells and macrophages (APC)
  3. APC present antigen and deliver other activation signals (cytokines)
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10
Q

what are high endothelial venules?

A

distinct compartments in lymph nodes

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11
Q

what happens to T cells that aren’t activated?

A
  • leave lymph node via cortical sinuses into lymphatics
    -reenter circulation
    -recycled for another day
    -short life span so die if cant eventually find an antigen
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12
Q

what happens when the T cells is activated?

A

-proliferation and activation of cells
-actively blocked from leaving that environment, have to expand there
-once expanded to certain level, they leave back to site where antigen is encountered and can deal with antigen

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13
Q

what are cell adhesion molecules (CAM)?

A

-mediate cell interactions
-molecules expressed on surface of T cells (chemokine receptors), binds ligand s (chemokines) expressed or released by other cells
-synthesised by lots of cells
-acts as sign posts fort cells to follow to work out where to go

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14
Q

what occurs with CAMs in close association to other cells?

A

-mediate cell/cell interactions
-hold cells on the APC so assess whether peptide Mac is capable of recepting

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15
Q

what are the different ways CAMs interact?

A

-naive T cell with HEV
-T cell with APC
-effector T cell and target cell

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16
Q

what happens with T cell contact with APC?

A
  1. T cells contact APC using CAMs
  2. TCR scans APC peptide/ MHC complexes
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17
Q

what happens if TCR doesn’t recognise the APC/MHC complex?

A

disengages

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18
Q

what happens if TCR recognises the APC/MHC complex?

A

signal released

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19
Q

how is the signal released?

A

-TCR gets signal through CD3 signalling complex
-causes T cell mediated response

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20
Q

what are occurs after cell contact with APC?

A

-increases affinity of CAM interactions
-T cell divides
-progeny differentiate to effector cells to produce T cell mediated responses

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21
Q

what 2 molecules are important in cell interactions?

A

LFA-1 and ICAM-1

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22
Q

what is the function of LFA-1 and ICAM-1?

A
  1. LFA-1 and ICAM-1 allow cellist stick together while decision is made about accepting
  2. CD4 holds cells together and interacts with class 2
  3. interaction takes place driving signal to alter this
  4. LFA-1 binds to ICAM-1 as a result of initial interactions - allows the two cells to be locked together and allow signalling to occur if correct peptide that TCR recognises
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23
Q

how does co-stimulation of signal 1 occur?

A
  • T cell receive signal through its CD3 complex
    -if TCR is recognising the peptide MHC complex -signal 1
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24
Q

how is signal 2 initiated?

A

-APC express co-stimulatory molecules (B7.1/B7.2 or CD80/CD86) that bind CD28 expressed by naive T cells and delivers signal 2 to the T cell

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25
Q

how is signal 3 delivered?

A

APCs release cytokines which bind cytokine receptors now unregulated on naive T cells which deliver signal 3

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26
Q

what are co-stimulatory molecules expressed on?

A

APCs only

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27
Q

what occurs once activated by the three signals?

A

-activated T cells now proliferate and express ICOS and CTLA-4
-need inbuilt way of turning off the activated T cells

28
Q

what is the function of ICOS?

A

binds ICOSL onAPC to induce cytokine secretion by T cells
related to CD28

29
Q

what is the function of CTLA-4?

A

shows stronger binding to B7.1/B7.2 than CD28
acts as an antagonist
highly related to CD28

30
Q

what does the binding of CTLA-4 to B7.1/2 on APC do?

A

delivers a negative signal to the activated T cell
dampens down/limits the T cell response

31
Q

what does a mutation in CTLA-4 cause?

A

-over-responsive immune system
-leads to autoimmune disease as T cell responses turned off

32
Q

how are the affects of the mutation reversed?

A

-the signals are blocked with antibodies
-makes T cells more responsive
-encourages body to overreact and keep responding to something
-stops immune response being turned off by tumours

33
Q

what do these mutations cause?

A

-type 1 diabetes

34
Q

what are the types of co-stimulatory molecules?

A

B7.1 (CD80) and B7.2 (CD86)

35
Q

how does the expression of co-stimulatory molecules vary?

A

-constitutive on mature dendritic cells
-inducible on macrophages and B cells

36
Q

what does activation of APC by pathogens induce?

A

co-stimulation expression so APC can provide signal 2 to activate T cells

37
Q

what is the danger signal?

A

-binding pathogen associated molecules activates the APC
-APC need to present something to T cells but also perceive danger
-ensures signal 2 to activate T cell mediated response only occurs during infection

38
Q

what is the response to the danger signal?

A

-ability to up regulate co-stimulatory molecules as a consequence of pattern recognition receptor engagement

39
Q

what is the purpose of signal 3?

A

decides what type of T cell/effector is going to be made

40
Q

what is the loop that occurs in signal 3?

A

the cytokine released from APC that stimulates the T cell to differentiate is also produced by that T cell- perpetuate themselves

41
Q

what T cell does IL-4 produce?

A

Th2 cells (t helper 2 cells)- mediate activation and maintain immune response

42
Q

what T cell does IL-12 and IFN-gamma produce?

A

Th1 cells

43
Q

what T cell does TGF-beta and IL-6 produce?

A

Th17 cells - mediate defensive mechanisms

44
Q

what T cell does IL-6 create?

A

Tfh cells - T follicular helper cells - development

45
Q

what does TGF-beta form?

A

T reg cells - control clonal expansion etc.

46
Q

what do APCs express?

A

MHC class 11 molecules

47
Q

what are the types of APCs?

A

-dendritic cells
-macrophages and B cells

48
Q

what is function of dendritic cells?

A

-to present antigens
-crucial for activation of naive T cells

49
Q

what is the function of macrophages and B cells?

A

-present antigen in order receive help from effector T cells

50
Q

what are the types of dendritic cell?

A
  1. myeloid (conventional DC2,3) - potent APC, activation of naive T cells
  2. plasmacytoid (pDC, DC6)- important in viral infection, secrete several type 1 alpha and beta interferons, express TLR 7 and 9 (sense viral antigens)
51
Q

what is the function of myeloid dendritic cells?

A

-initiate T cell responses
-bone marrow derived
-immature form found in epithelia
-engulfs by phagocytosis
-doesn’t express co-stimulatory molecules until activated
-migrate to lymph node following danger signal activation
-sense danger as have pattern recognition receptors
-upregulate B7 if sense danger

52
Q

what occurs after activation of DC?

A

-mature DC (2,3) found in T cell areas of lymphoid tissues
-DC MHC class 1 and 2 will be loaded with peptides from pathogens they encountered in peripheral tissues
-levels of co-stimulatory molecules very high
-express high levels of adhesion molecules - efficient activators of naive T cells

53
Q

what is the process after activation?

A
  1. immature dendritic cells in peripheral tissues encounter pathogens and are activated by PAMPs
  2. DC eats bacteria, chops up and puts on surface in association with class 2
  3. move towards lymph nodes
  4. cells go to site where needed most
  5. b7 molecules on surface
  6. DC releases cytokines to produce signal 3
54
Q

what is cross presentation?

A

some specialised DC (DC 1) take up proteins from outside and instead of presenting on class 2, they present on class 1

55
Q

what is the benefit of cross presentation?

A

-allows DC to activate naive CD8 T cells
-then these CD8 effector cells can kill infected cells that aren’t APC so not expressing co-stim

56
Q

what are the features of macrophages?

A

-function as scavengers/killers of pathogens
-highly phagocytic
-express MHC class 2 and B7 which increases following T cell help
resident in many tissues at peripheral sites
-once activated by T cells, secrete many inflammatory cytokines

57
Q

what are the features of B cells?

A

-poor at phagocytosis
-internalise soluble antigens for processing and presentation by BCR-upregulates co-stim on B cells so they become APCs that deliver signal 2 and express class 2 scan deliver signal 1 t to cells and also signal 2 and 3
-found in lymph node presenting to T cells

58
Q

how do B cells act as antigen specific APCs?

A

-only antigen specific B cell binds the antigen
-specific antigen efficiently internalised by receptor mediated endocytosis
-high density of specific antigen fragments presented

59
Q

what is a key cytokine in T cell survival ?

A

IL-2 (interleukin-2)

60
Q

what is the function of IL-2?

A

-essential for T cell activation
-cytokine that T cells make themselves to cause them to proliferate
-potent autocrine T cell growth factor

61
Q

how does high affinity for IL2 cause proliferation?

A

-naive T cells express low affinity of IL2
-once T cells activated they express high affinity IL-2 receptors and secrete IL-2
-IL-2 binding to IL-2R on activated T cells = lots of T cell proliferation

62
Q

what is the function of IL-2?

A

-allows rapid division of T cells
-expands population of antigen specific activated T cells - happens downstream of signals
-need to make lots of copies with unique receptor deed to bind to specific peptide
-lots of levels of control are in place
-target of immunosuppressive drugs eg. cyclosporin

63
Q

once activated, what do T cells differentiate into?

A

effector T cells
-CD8 cells acquire cytotoxic activity (kills cells expressing peptide/MHC class 1 complexes)
-CD4 cells function by secreting cytokines, recognise peptide/MHC class 11 complexes

64
Q

what do effector T cells do?

A

-display effector function when TCR engaged - no longer require stimulation, change expression of adhesion molecules
-no longer enter lymph nodes but enter tissues via activated endothelia at sites of infection and inflammation - migrate nowhere needed

65
Q

how are CD8+ T cells activated?

A

-requires high levels of co-stimulator activity
-can be activated directly by infected or cross presenting APC or may require additional help from CD4+ T cells