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MICR3305 > 10 - T Cell Effector Responses > Flashcards

10 - T Cell Effector Responses Flashcards

1
Q

T cell pathway

A
  • T cell precursor rearranges its T cell receptor genes in the thymus
  • Immature T cells that recognise self MHC receive signals for survival. Those that interact strongly with self antigen are killed
  • Mature T cells encounter foreign antigens in the peripheral lymphoid organs and are activated
  • Activated T cells proliferate and eliminate infection
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2
Q

Naive T cells

A
  • T cell has not previously encountered its cognate antigen
  • Antigen is brought to lymph node by dendritic cell that has sampled antigen in periphery
  • Naïve T cell that encounters cognate antigen is activated
    and undergoes clonal expansion, differentiates into effector or memory cells
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3
Q

Cognate antigen

A

Antigen that best fits the specific T cell receptor

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4
Q

Effector T cells

A
  • Enter circulation and traffic to sites of infection in peripheral tissues
  • Effector cells that encounter antigen in the periphery are further activated to mediate their effector functions
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5
Q

What is activation and movement of T cells mediated by

A

Cytokines and chemokines

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6
Q

3 major processes that must occur after antigen recognition

A
  • Produce cytokines and cytokine receptors (e.g. IL-2) –> Proliferation
  • Proliferate and undergo clonal (TCR with same specificity) expansion
  • Differentiation into effector (short lived) or memory (long lived) cells
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7
Q

Lymphocytes in blood entering lymphoid tissue

A
  • Cross walls of high endothelial venules (HEV)
  • CCL21 is expressed by HEV and stromal cells of lymphoid tissues and binds CCR7 on naïve T cells
  • Contact of naïve T cells with CCL21 in the HEV causes the integrin LFA-1 on the naïve T cell to become activated, increasing its affinity for ICAM-1
  • Activated LFA-1 binds tightly to ICAM-1
  • Lymphocyte migrates into lymph node by diapedesis
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8
Q

What cells stimulate naive T cells

A

B7 expressing DCs

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9
Q

What molecule indicates that a DC has seen an antigen

A

B7

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10
Q

Process of T cells encountering an antigen

A
  • Naïve T cells enter lymph nodes from arterial blood via specialised endothelial cells called high endothelial venues (HEV)
  • T cells migrate into paracortical areas where they encounter dendritic cells
  • T cells that do not encounter cognate antigen leave node via lymphatics and return to circulation
  • T cells that encounter cognate antigen become activated to proliferate into effector cells. They lose ability to exit lymph node
  • After a few days effector cells regain ability to leave nodes and leave via efferent lymphatics and enter circulation
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11
Q

Naive T cells and dendritic cell interactions

A
  • T cell initially binds DC through low affinity LFA-1 : ICAM-1 interactions
  • Subsequent binding of T cell receptors sends signal to LFA-1
  • Conformational change in LFA-1 increases affinity and prolongs cell to cell contact
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12
Q

Nursery

A

Satellite DC maintains contact with all clones

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13
Q

How long does it take for activated effector T cells to leave the lymph node after arrival of antigen

A

5 days and leave via efferent lymphatics

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14
Q

Trapping

A

All naïve T cells specific for a particular antigen can be trapped by that antigen (presented via DC) in node within 2 days

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15
Q

3 signals delivered by APCs to activate T cells

A
  1. Antigen presentation (MHC/peptide to TCR): activation
  2. Co-stimulatory molecules: Survival
  3. Cytokines: Differentiation
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16
Q

Antigen presentation signals

A
  • MHC class 1/peptide to CD8+ T cell
  • MHC class 2/peptide to CD4+ T cell
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17
Q

Co-stimulatory molecules

A
  • CD28 on T cell to B7 (CD80/ CD86) on DC
  • CTLA-4 on T cell to CD80/CD86 on DC for homeostasis
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18
Q

Cytokine signals in activation

A
  • T cell proliferation (IL-2)
  • T cell lineage differentiation (cytokines produced by APC, mostly DC)
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19
Q

Examples of cytokines involved in activation of naive T cells

A
  • IL-4
  • IL-6
  • IL-12
  • TGF-β
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20
Q

Variation in signal 3 (cytokines)

A

Causes naive T cells to acquire several distinct types of effector function

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21
Q

Treg Cells

A

Down-regulate effector responses

22
Q

Tfh Cells

A

Found in germinal centre lymph nodes, assist B cells

23
Q

Th17 cells

A

Importnat in neutrophil function

24
Q

Th1

A

Supporting cell mediated immunity (macrophages)

25
Q

Th2

A

Supporting cell mediated immunity (macrophages) and support B cells

26
Q

Which two cytokines down regulate T cell immunity

A
  • TGF-β
  • IL-10
  • Secreted by Treg cells
27
Q

Cytokines and transcription factor that cause differentiation of Treg cells

A
  • TGF-β
  • FoxP3
28
Q

Cytokines and transcription factor that cause differentiation of Tfh cells

A
  • IL-6
  • Bcl6
29
Q

Cytokines and transcription factor that cause differentiation of Th17 cells

A
  • TGF-β and IL-6
  • RORγT
30
Q

Cytokines and transcription factor that cause differentiation of Th1 cells

A
  • IL-12 and IFN-γ
  • T-bet
31
Q

Cytokines and transcription factor that cause differentiation of Th2 cells

A
  • IL-4
  • GATA3
32
Q

Why have human evolved multiple subsets of T cells

A

To protect against different classes of pathogens

33
Q

What do Tfh cells secrete

A

IL-21 and ICOS

34
Q

What do Th17 cells secrete

A

IL-6 and IL-17

35
Q

What do Th1 cells secrete

A

IL-2 and IFN-γ

36
Q

What do Th2 cells secrete

A

IL-2 and IL-5

37
Q

How do CD8+ cytotoxic T cells kill target cells

A
  • A pore is created in target cell by CTL perforin
  • Granzymes delivered through pore induce caspase- dependent apoptosis pathways
38
Q

CD4 T cell help in activating CD8 T cells

A
  • APC stimulates effector CD4+ T cell to induce expression of CD40L and IL-2
  • Effector CD4+ T cell recognises antigen on the APC and is triggered to induce increased levels of co-stimulatory activity on the APC (increased B7 and expression of 4-IBBL)
  • 4IBBL ligates 4-IBB on CD8+ T cell (this enhances activation of CTL)
  • The CD4+ T cell also produces IL-2 that drives proliferation of CD8+ T cells
39
Q

TCR ligation with MHC/peptide complex in absence of CD28/B7 co-stimulation

A
  • Induces anergy (state of unresponsiveness that is irreversible)
  • Through decreased signalling by induction of GRAIL and activation of Cbl
40
Q

Role of CTLA-4

A
  • Contraction and re-establishment of homeostasis
  • CTLA-4 binds B7 more avidly than CD28 and delivers inhibitory signals to activated T cells
41
Q

How does CTLA-4 outcompete CD28

A

A distinct binding orientation allows one dimer of CTLA-4 to bind two different B7 dimers, providing for high avidity clustering

42
Q

CTLA-4 In cancer therapy

A
  • Binding of B7 to CTLA-4 inhibits T cell function
  • Anti–CTLA-4 antibodies block CTLA-4 binding and prevent inhibition of T cell function (checkpoint inhibitor)
43
Q

When does activation and co stimulation occur

A

At time of priming (co-stimulation not required for recognition of antigen at infection site)

44
Q

Th1 cell function

A
  • Macrophage activation
  • Complement binding and opsonising IgG antibodies
45
Q

Responses of activated macrophages to Th1 cells

A
  • Enhanced killing of phagocytosed bacteria
  • Secretion of inflammatory cytokines
  • Increased expression of molecules required for T cell activation
46
Q

Function of Th2 cells

A
  • Antibody production (helminth parasites too big to be phagocytosed)
  • Mast cell degranulation
  • intestinal mucus secretion and peristalsis
  • Eosinophil activation
  • Alternative macrophage activation (enhanced tissue repair)
47
Q

Th2 cytokines role in macrophage activation

A

Th2 cytokines inhibit classical macrophage activation (microbicidal) and stimulate the alternative pathway of macrophage activation (anti-inflammatory, tissue repair)

48
Q

Function of Th17 cells

A
  • Innate response
  • Inflammation, neutrophil response
  • Anti-microbial peptides
  • Increased barrier function
49
Q

Regulatory T cells (Treg) function

A

Suppress and prevent immune responses (eg. to self antigens: maintains tolerance) through inhibition of T cell activation and T cell effector function

50
Q

Decline of immune response

A
  • Once immune response is over, system must return to steady state (homeostasis)
  • Once infection is cleared, cells are deprived of stimuli and survival signals
  • Cells die of apoptosis
  • Response subsides within 1-2 weeks after infection is eradicated
  • Pool of memory cells remains

MICR3305 (24 decks)

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