Lecture 11 - Activation of T Lymphocytes Flashcards
What is the general mechanism of naïve T cell activation?
L11 S5
- 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.
What signals are required for T cell activation and differentiation?
L11 S9
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
What molecules are involved in generation of signal 1 for T cell activation?
L11 S11
Ag-MHC2/1 complex binds TCR-CD4/8-CD3 complex generating signal 1
What molecules are involved in generation of signal 2 for T cell activation?
L11 S14-16
Activated APCs express surface CD80/86 which binds T cell surface CD28 to generate costimulatory signal 2
What B7CD28 family receptors are there, what are their ligand, and what is their function?
L11 S20
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
What is the CTLA-4 checkpoint?
L11 S22
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.
What is the PD-1 checkpoint?
L11 S23
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.
What molecules generate signal 3 for Th1 cells?
L11 S26
IL-12 binds IL-12R
IL-12R activates STAT4
STAT4 stimulate expression of T-bet
Cell differentiates into Th1 cell
What molecules generate signal 3 for Th2 cells?
L11 S26
IL-4 binds IL-4R
IL-4R activates STAT6
STAT6 stimulates expression of GATA3
Cell differentiates into Th2 cell
What molecules generate signal 3 for Th17 cells?
L11 S26
IL-6 binds IL-6R
IL-6R activates STAT3
STAT3 stimulates expression of RORγT
Cell differentiates into Th17 cell
What molecules generate signal 3 for T(reg) cells?
L11 S26
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
What are superantigens and what do they do?
L11 S28
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)
What are the biological actions of IL-2 and its functional properties of for activated T cell and T(reg) cells?
L11 S33
- 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
What is the function of CD69 in T cell activation?
L11 S36
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.
What is the function of IL-2Rα in T cell activation?
L11 S38
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.
What is the function of CD-40L in T cell activation?
L11 S39
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.
What factors are responsible for the decline of T cell responses
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
What are the different models of how memory T cells are formed?
L11 S43
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
What are characteristics of memory T cells?
L11 S44
- 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
What transcription factors stimulate differentiation into memory T cells.
L11 S44
T-bet:
-drives differentiation of CD4+ cells
Blimp-1:
-promotes the generation of memory cells
What are the different types of memory T cells and their characteristics?
L11 S45;49
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
What are the stages of memory T cells frequency/function with regards to the age of the individual?
L11 S47
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
What is the mechanism of immunosenescence?
L12 S11
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
What signature cytokine(s) do Th1 cells produce?
L12 S19
-IFN-γ
What signature cytokine(s) do Th2 cells produce?
L12 S19
- IL-4
- IL-5
- IL-13
What signature cytokine(s) do Th17 cells produce?
L12 S19
- IL-17A
- IL-17F
- IL-22
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
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
What cytokines stimulate Th1 differentiation and what transcription factors do they activate?
L12 S21
Cytokines:
- IL-12 (DCs)
- IFN-γ (NK cells)
Transcription factors:
- T-bet (IL-12)
- STAT4 (IL-12)
- STAT1 (IFN-γ)
What cytokines stimulate Th2 differentiation and what transcription factors do they activate?
L12 S21
Cytokines:
-IL-4 (CD4+ T cell, mast cell, eosinophil)
Transcription factors:
- GATA-3
- STAT6
What cytokines stimulate Th17 differentiation and what transcription factors do they activate?
L12 S21
Cytokines (all from DCs):
- IL-1
- IL-6
- IL-23
- TGF-β
Transcription factors:
- RORγt
- STAT3
What transcription factor is responsible for development of T(reg) cells?
L12 S28
FOXP3
