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Immunology and Infection > CD4 T cells > Flashcards

CD4 T cells Flashcards

1
Q

what are the different subsets of CD4 T cells?

A
  • Th1
  • Th2
  • Th17
  • Treg
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2
Q

how are the different CD4 T cells distinguished?

A

by their signature cytokines

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3
Q

what is the signature cytokine of Th1?

A

IFN-y

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4
Q

what is the signature of Th2?

A

IL-4, IL-5

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5
Q

why are different subsets of CD4 T cells needed?

A

different pathogens need different immune responses

- the different subsets coordinate different distinct immune responses

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6
Q

what are cytokines?

A
  • proteins secreted by immune cells and non-immune cells that bind to receptors
  • secreted proteins that influence immune function
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7
Q

what is signal?

A

polarising cytokines

- innate immune cells evolved to produce different polarising cytokines following recognition of different pathogens

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8
Q

how does a CD4 T cell differentiate to a Th1?

A
  • DC recognises PAMP through PRR (eg bacteria)
  • DC presents peptide and produces IL-2
  • naive CD4 T cell has an IL-2R
  • type 1 innate lymphoid also has a IL-2R and produces IFN-y
  • Binds to IFN-yR on CD4 T cell
  • naive CD4 T cell becomes a TH1
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9
Q

what is Th1 cell characterised by?

A

high levels of IFN-y production

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10
Q

how does a CD4 T cell differentiate into a Th2?

A
  • parasitic worm secretes molecules
  • DC presents antigens on MHC II
  • parasitic worms cause tissue damage
  • tissue damage detected by stromal cells
  • produces cytokines that induce ILC2
  • ILC2 produces IL-4
  • naive CD4 T cell differentiates to a Th2 cell in response to the two signals
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11
Q

what is the general pathway of a polarising cytokine inducing intracellular signalling pathways in CD4 T cells?

A
  • cytokine binds receptor
  • conformational change
  • Activates JAKs
  • phosphorylates cytokine receptor
  • act as docking sites for STATs
  • bring STATs close to JAKs
  • JAKs phosphorylate STATs
  • STATs move into nucleus
  • act as transcription factors
  • interact with promoters
  • results in expression of cytokines, cytokine receptors and transcription factors
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12
Q

what s the lineage specific transcription factor of Th1?

A

T-bet

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13
Q

what is the lineage specific transcription factor of Th2?

A

GATA3

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14
Q

what happens as a result of IL-2 binding to the IL-2 receptor in Th1 cells?

A
  • conformational shift
  • activates JAKs
  • docking sites for STAT4, gets phosphorylated
  • STAT4 migrates to nucleus
  • binds to promoter of T-bet
  • causes expression of IL-2R
  • causes expression of IFN-y
  • T-bet binds and stabilises expression
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15
Q

what happens as a result of IL-4 binding to the IL-4 receptor on Th2 cells?

A
  • conformational shift
  • activates JAKs
  • phosphorylates STAT6
  • moves to the nucleus
  • interacts with the promoters of these 4 genes (and causes expression):
    1. GATA3 2. IL-4R 3. IL-4 4. IL-5
  • GATA3 binds and stabilises expression
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16
Q

what are Th1 good against?

A

bacteria, viruses, intracllular protozoa

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17
Q

what are Th2 good against?

A

parasitic worms

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18
Q

what is the general function of a CD4 T cell?

A
  • cause class switching in B cells
  • stronger activation of macrophages
  • stronger CD8+ activation
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19
Q

what is B cell class switiching?

A
  • antibodies have different isotypes
  • different variable and constant regions
  • start as IgM or IgD
  • class switch to become IgG, IgE, IgA
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20
Q

why is the antibodies different heavy chain constant regions important?

A
  • bind to different Fc receptors

- different ability to activate the complement cascade

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21
Q

how do CD4 T cells cause class switching in B cells generally?

A

through their signature cytokines

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22
Q

how does Th1 cause class switching?

A
  • produces IFN-y
  • binds to IFN-yR on B cells
  • induces B cells to class switch to IgG2a
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23
Q

how does Th2 cause class switching?

A
  • produces IL-4
  • binds IL-4R on B cells
  • induces class switch to IgG1 or IgGE
  • when class switched the antibodies bind to different immune cells
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24
Q

after being class switched by Th2 what affects do these antibodies have?

A
  • bind to different immune cells
  • eg in response to parasitic worms-IL-4-IL-4R- IgE produced, eosinophils and mast cells expresses a high affinity receptor (FceR) for IgE
  • also produces IL-5 which is a growth and survival factor for eosinophils
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25
Q

what is FceR?

A
  • binds to the Fc region of the antibody

- now described as being pre-armed with antibody

26
Q

what happens when parasites produce factors that bind to the IgE receptors?

A
  • can bind to the antibody on the surface
  • cross links the Fc receptors and causes the activation of eosinophils and mast cells and their degranulation
  • leads to damaging of the parasite
27
Q

what do naive CD4 T cells express?

A
  • express L selectin which allows it to circulate into the lymph nodes
  • express adhesion molecules like LFA1
28
Q

what happens when naive CD4 T cells become activated?

A
  • they have a different surface phenotype
  • lose expression of L-selectin (it is cleaved off)
  • increase in integrins
  • start expressing CD40L
29
Q

why is CD40L needed?

A

involved in the interaction of macrophages and dendritic cells

30
Q

where do CD4 T cells migrate?

A

from the blood to inflamed tissues

31
Q

how do CD4 T cells migrate from the blood to inflammed tissues?

A
  • macrophages release inflammatory cytokines and chemokines
  • increase expression of ICAM1 and VCAM1
  • VCAM1 binds VLA-4
  • activated T cell adheres and can migrate into the tissue
  • helps macrophages
32
Q

why is it important to note that macrophages are also APCs?

A
  • digest and present on MHC II to Th1 cells

- get cross talk

33
Q

how do Th1 cells help macrophages?

A
  • produce IFN-y which binds to IFN-yR on macrophages
  • produces CD40L which binds to CD40
  • this elicits a membrane associated signal
  • activates macrophages to kill intracellular pathogens
34
Q

how do DCs activate CD8 T cells?

A
  • through the expression of peptide bound MHC I

- however, the activation is suboptimal

35
Q

how does a CD4 T cell help to full activate a CD8 T cell?

A
  • DC presents peptide MHC II
  • activates CD4
  • produces large amounts of IL-2
  • IL-2 nourishes CD8
  • can also help through the CD40L
  • the active CD4 T cells licence the DC to fully activate the CD8 T cell
36
Q

how does the CD4 T cell help the CD8 T cell with the CD40L?

A
  • cross links with CD40 on DC
  • causes a signalling cascade from the DC
  • causes the DC to express new co-stimulatory molecules (4-IBBL) which binds to the co-receptor (4-IBB)
  • results in the strongest CD8 activation
37
Q

what signature cytokine do Th17 cells produce?

A

IL-17

38
Q

what is the role of a Th17 cell?

A
  • to initiate effector immune response against pathogens that cannot be cleared by Th1 or Th2 cells
  • target extracellular bacteria and fungi
39
Q

how are Th17 cells induced?

A
  1. PAMPs bind to DC PRRs
  2. DC produces signal 3 which activates TGF-B and IL-6
  3. Initial Th17 differentiation
  4. DCs also produce IL-23; IL-23 binds to IL-23R
40
Q

what happens when PAMPs bind to DC PRRs during Th17 differentiation?

A
  • antigen uptake
  • digested into peptides
  • MHC II presentationss
  • PRRs toll like receptors and C type lectins
41
Q

what is the role of TGFB and IL-6 during Th17 differentiation?

A
  • IL-6: inflammatory cytokine. Binds to receptors on endothelial cells and express more adhesion molecule
  • Active TGFB: converts inactive TGFB in the environment to active TGFB (cleaves it)
42
Q

what effect does IL-23 have when it binds to IL-23R during Th17 cell differentiation?

A
  • stabilised the phenotype

- promotes survival and expansion of Th17 cells

43
Q

what happens during the STAT3 intracellular signalling pathway when IL-6 binds to the IL-6R on Th17?

A
  • conformational shift
  • activates JAKs
  • phosphorylates the IL-6R
  • STAT3 docks and is phosphorylated
  • STAT3 migrates to the nucleus and interacts with the promoters: 1. binds RORyt 2. more expression of IL-23R 3. more expression of IL-17
  • STAT3 alone generates a small amount of expression
44
Q

what happens during the TGF B intracellular signalling pathway when IL-6 binds to the IL-6R on Th17?

A
  • not as well understood
  • TGFB - TGFB receptors - activates SMAD proteins
  • they go to the nucleus and interact with the same genes as STAT3
  • get full expression of Th17 genes: RORyt, IL-23R and IL-17
  • RORyt binds back and stabilises expression
45
Q

how does Th17 become activated?

A
  • by DCs in the T cell zone causing Th17 differentiation

- tissue macrophage reactivate Th17 cells through MHC II

46
Q

how do Th17 cells get into the site of infection?

A
  • become activated by DCs
  • leave the lympho node
  • gain VLA4 and increase LFA1
  • interacts with adhesion molecules and chemokines
  • enters the tissue
47
Q

what is the function of the IL-17 chemokine that Th17 cells release?

A
  • bind to IL-17R
  • expressed by fibroblasts and epithelial cells
  • these stromal cells produce lots of CXCL8
  • attracts neutrophils
48
Q

what is the role of Th17 cells?

A

inducing stromal cells to recruit neutrophils to the site of infection

49
Q

what is the role of Tregs?

A
  • turn of the immune response

- they are inflammatory and potentially pathogenic

50
Q

what are the 2 types of Tregs?

A

natural Treg and induced Treg

  • have alpha beta TCR
  • have CD4 on surface
  • inhibit effector T cells
  • inhibits APC
  • inhibits other immune cells
51
Q

what cause natural Tregs to differentiate in the thymus?

A
  • nTregs develop in the thymus in response to stronger than normal signal through TcR stimulation
  • thymocyte upregulates FoxP3
52
Q

what is meant by a stronger than normal reaction in nTregs?

A
  • bind to self-peptide MHC II not strong enough that they are autoreactive but to an extent that it can become activated regulatory cytokines
53
Q

what is hypothesised about nTregs?

A

that nTregs are all self-reactive - inhibit strongly auto-reactive T cells that could cause autoimmunity

54
Q

what causes induced Tregs to differentiate in the periphery?

A
  • start as naive T cells
  • encounters DC presenting its antigen and co-stimulation, able to activate TGFB in the absence of an inflammatory signal
55
Q

what is the default state for T cell that encounters a DC presenting its antigen in the absence of an inflammatory signal?

A

this T cell will upregulate FoxP3 and differentiate into iTreg

56
Q

what is the difference between the activation of an iTreg and Th17?

A
  • iTreg needs TGFb (immune suppression)
  • Th17 needs TGFB and IL-6 (inflammation)
  • pathogens induce inflammatory cytokines that switch immune suppression to an inflammatory response
57
Q

how do Tregs suppress the immune response?

A

through cell surface molecules and secretion of immune supressive cytokines

58
Q

what cell surface molecules do Tregs use to suppress the immune response?

A
  1. Tregs express high levels of CTLA-4

2. Tregs express high levels of IL-2 receptors

59
Q

what is the role of CTLA-4 in Treg immune suppression?

A
  • high affinity to CD80/CD86 on DCs
  • sequesters them away from naive T cells
  • stops DCs providing signal 2 to naive T cells (anergy)
  • CTLA-4 can physically rip CD80/CD86 from APCs
60
Q

what is the role of IL-2R in Treg immune suppression?

A

can suck the IL-2 away from the activated T cells to stop their proliferation

61
Q

what is the role of the immunosuppressive cytokines IL-10 and TGFB in Tregs?

A
  1. inhibit IL-12 production by DCs
  2. Reduce mHCII and CD80/CD86 levels on DCs
  3. inhibit T cell proliferation
  4. generate more Tregs (TGFB)
62
Q

how have Foxp3(+) regulatory T cells been shown to be essential?

A
  • natural mutations to Foxp3 on X chromosome = IPEX syndrom
  • they lack Tregs
  • fatal early onset and autoimmune disease in males

Immunology and Infection (13 decks)

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