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(J) Immunology Test 2 > Lecture 11 - Activation of T Lymphocytes > Flashcards

Lecture 11 - Activation of T Lymphocytes Flashcards

1
Q

What is the general mechanism of naïve T cell activation?

L11 S5

A
  • naïve T cells migrate to LN
  • naïve T cells interact with mature dendritic cells which have brought Ags
  • if naïve T cell interacts with Ag specific to its TCR it release IL-2 and is activated into effector T cell
  • it either remains in lymphoid organ to help B cells or migrate to site of infection to help activated macrophages.
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2
Q

What signals are required for T cell activation and differentiation?

L11 S9

A

Signal 1:

  • Ag recognition
  • Ag presentation by dendritic cells for naïve T cells or by Mφ/B cells for effector T cells

Signal 2:
-costimulation

Signal 3:
-cytokines

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3
Q

What molecules are involved in generation of signal 1 for T cell activation?

L11 S11

A

Ag-MHC2/1 complex binds TCR-CD4/8-CD3 complex generating signal 1

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4
Q

What molecules are involved in generation of signal 2 for T cell activation?

L11 S14-16

A

Activated APCs express surface CD80/86 which binds T cell surface CD28 to generate costimulatory signal 2

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5
Q

What B7CD28 family receptors are there, what are their ligand, and what is their function?

L11 S20

A

CD28:

  • ligand: B7-1 (CD80) and B7-2 (CD86)
  • costimulation of T cells (signal 2)
  • expressed constitutively

CTLA-4:

  • ligands: B7-1 (CD80) and B7-2 (CD86)
  • inhibition of T cell activation
  • induced exression

ICOS (Inducible T-cell Costimualtor):

  • ligand: ICOS-L (CD275)
  • costimulation of effector/regulatory T cells to produce follicular helper T cell
  • induced expression

PD-1 (program death-1):

  • ligands: PD-L1 (B7-H1/CD274) and PD-L2 (B7-DC/CD273) on APCs and cancer cells
  • negative regulation of T cells
  • induced expression
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6
Q

What is the CTLA-4 checkpoint?

L11 S22

A

Signal 1 and 2 stimulates the transport of vesicular CTLA-4 to the plasma membrane.

The amount of CTLA-4 transported is proportional to the strength of signal 1 and 2.

Because TCR and CD28 are expressed constitutively, CTLA-4 acts to dampen the signals generated by these two so T cells are activated at a consistent level.

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7
Q

What is the PD-1 checkpoint?

L11 S23

A

Activated T cells express PD-1.

Inflammatory signals, such as IFN-γ, in tissues induce expression of PD-L1.

Binding of PD-1 to PD-L1 causes downregulation of T cells to regulate collateral damage.

Excess PD-1 expression can induce an anergic state.

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8
Q

What molecules generate signal 3 for Th1 cells?

L11 S26

A

IL-12 binds IL-12R

IL-12R activates STAT4

STAT4 stimulate expression of T-bet

Cell differentiates into Th1 cell

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9
Q

What molecules generate signal 3 for Th2 cells?

L11 S26

A

IL-4 binds IL-4R

IL-4R activates STAT6

STAT6 stimulates expression of GATA3

Cell differentiates into Th2 cell

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10
Q

What molecules generate signal 3 for Th17 cells?

L11 S26

A

IL-6 binds IL-6R

IL-6R activates STAT3

STAT3 stimulates expression of RORγT

Cell differentiates into Th17 cell

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11
Q

What molecules generate signal 3 for T(reg) cells?

L11 S26

A

TGF-β binds TGF-βR

TGF-βR activates SMAD-2 and SMAD-4

SMAD-2 and SMAD-4 stimulates expression of FOXP3

Cell differentiates into T(reg) cell

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12
Q

What are superantigens and what do they do?

L11 S28

A

Superantigens are extremely strong T cell mitogens causing uncontrolled T cell stimulation.

They are not processed into peptides and bind MHC class II to β subunit of TCRs.

Causes massive production of TNF, IL-1, and IL-2.

Examples:

  • staphylococcal enterotoxins (SE)
  • toxic shock syndrome toxin (TSST)
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13
Q

What are the biological actions of IL-2 and its functional properties of for activated T cell and T(reg) cells?

L11 S33

A
  • autocrine growth factor for CD4+ and CD8+
  • potentiates cytotoxicity of CD8+ T cells and NK cells
  • co-simulates production of IL-4, IL-5, and IFN-γ

Activated T cells:

  • stimulates survival by inducing anti-apoptotic protein Bcl-2
  • stimulates cell cycle progression by degrading cell cycle inhibitor p27
  • stimulates differentiation

T(reg):

  • necessary for survival of function of T(reg) cells
  • without IL-2 immune self-tolerance is lost
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14
Q

What is the function of CD69 in T cell activation?

L11 S36

A

In order to leave LNs, T cells and B cells require sphingosine 1-phosphate receptor (S1PR1) which causes chemotaxis towards sphingosine 1-phosphate in the lymph.

CD69 is expressed after T cell activation and reduces expression of S1PR1, preventing T/B cells from leaving the LNs.

Because of this, naïve T/B cells are retained in the LNs while receiving signals for proliferation and differentiation.

After cell division, CD69 expression is decreased and the activated T cell re-express S1PR1 allowing them to leave the LN.

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15
Q

What is the function of IL-2Rα in T cell activation?

L11 S38

A

IL-2Rα (also known as CD25) is only expressed in activated T cells while IL-2Rβγc is expressed constitutively on naïve T cells.

Only after the T cell is activated will it have IL-2Rαβγc complexes which have a high affinity for IL-2 and stimulates T cell proliferation.

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16
Q

What is the function of CD-40L in T cell activation?

L11 S39

A

CD-40L expression of T cells is stimulated y Ag recognition.

CD-40L binds CD-40 present on DCs causing them to express B7 (CD80/86) and secrete certain cytokines.

DC B7 binding to T cell CD28 generates signal 2 and cytokines binding receptors on T cells generates signal 3.

17
Q

What factors are responsible for the decline of T cell responses

A

Elimination of Ag leads to a decrease of IL-2 and costimulation.

This causes the level of anti-apoptotic factors to drop and IL-2 starvation triggers intrinsic pathway of apoptosis.

Other factors:

  • CTLA4 and PD-1 inhibitory receptors
  • death receptors of TNFRI and Fas
  • products of T(reg) cells
18
Q

What are the different models of how memory T cells are formed?

L11 S43

A

Linear Model:

  • naïve T cells differentiate into effector T cell
  • most effector T cells die but those that remain are memory T cells
  • (more supported)

Branched Differentiation Model:
-naïve T cells either differentiate into effector T cells or memory T cells

19
Q

What are characteristics of memory T cells?

L11 S44

A
  • generated in response to T-cell response to Ag
  • survive for long periods of time (years to whole life time)
  • most abundant lymphocyte population in lifetime
  • reside primarily in tissues, including secondary lymphoid organs
20
Q

What transcription factors stimulate differentiation into memory T cells.

L11 S44

A

T-bet:
-drives differentiation of CD4+ cells

Blimp-1:
-promotes the generation of memory cells

21
Q

What are the different types of memory T cells and their characteristics?

L11 S45;49

A

Resident memory T cells (T(RM) cells):

  • produce IFN-γ and TNF
  • specific for previously encountered pathogens/Ags in the epithelial barrier they reside in

Central memory T cells (T(CM) cells):

  • circulate in blood and home to LN and spleen
  • express cytokine receptors CCR7 and L-selectin
  • proliferate (produce IL-2) upon re-exposure to Ag and produce many effector cells

Effector memory T cells (T(EM) cells):

  • do not produce IFN-γ/TNF or become cytotoxic
  • circulate in blood and can enter tissue to become T(RM) cells
22
Q

What are the stages of memory T cells frequency/function with regards to the age of the individual?

L11 S47

A

Memory generation:

  • age 0-~20
  • gradual increase in memory T cell population
  • gradual decrease in infection susceptibility

Memory homeostasis:

  • age 30-65
  • homeostatic state of memory cell population and disease susceptibility

Immunosenescence:

  • age >65
  • memory cell population remains the same
  • disease susceptibility increases
23
Q

What is the mechanism of immunosenescence?

L12 S11

A

Naïve T cell generation decrease due to thymic involution

Senescent changes in memory cells due to loss of CD28 expression (loss of costimulation/signal 2) which results in:

  • decreased proliferative capacity
  • shortened telomeres
  • reduced TCR repertoire
  • enhanced cytotoxic activity
24
Q

What signature cytokine(s) do Th1 cells produce?

L12 S19

A

-IFN-γ

25
Q

What signature cytokine(s) do Th2 cells produce?

L12 S19

A
  • IL-4
  • IL-5
  • IL-13
26
Q

What signature cytokine(s) do Th17 cells produce?

L12 S19

A
  • IL-17A
  • IL-17F
  • IL-22
27
Q

What cytokines are produced by T cells and what are their functions?

IL-2, IL-4, IL-5, IL-13, IL-17, IL-21, IL-22, IFN-γ, and TGF-β

L12 S20

A

IL-2: T cell proliferation/survival
IL-4: B cell Ig switching to IgE
IL-5: activation of eosinophils
IL-13: B cell Ig switching to IgE; asthma
IL-17: stimulates acute inflammation
IL-21: autocrine amplification of Th17
IL-22: maintenance of epithelial barrier function
IFN-γ: activates macrophages
TGF-β: inhibition of Th1/2 cell activation

28
Q

What cytokines stimulate Th1 differentiation and what transcription factors do they activate?

L12 S21

A

Cytokines:

  • IL-12 (DCs)
  • IFN-γ (NK cells)

Transcription factors:

  • T-bet (IL-12)
  • STAT4 (IL-12)
  • STAT1 (IFN-γ)
29
Q

What cytokines stimulate Th2 differentiation and what transcription factors do they activate?

L12 S21

A

Cytokines:
-IL-4 (CD4+ T cell, mast cell, eosinophil)

Transcription factors:

  • GATA-3
  • STAT6
30
Q

What cytokines stimulate Th17 differentiation and what transcription factors do they activate?

L12 S21

A

Cytokines (all from DCs):

  • IL-1
  • IL-6
  • IL-23
  • TGF-β

Transcription factors:

  • RORγt
  • STAT3
31
Q

What transcription factor is responsible for development of T(reg) cells?

L12 S28

A

FOXP3

(J) Immunology Test 2 (9 decks)

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