Activation of T Lymphocytes Flashcards
Where does activation of naive T cells occur if they encounter TCR-specific Ags?
LNs
What cell presents Ags to naive T cells in LNs?
Ags that are transported to LNs from the periphery by mature (activated) DCs.
What are the two possible functions of activated T cells that differentiate into effector cells?
- remain in the lymphoid organs to help B lymphocytes
- migrate to sites of infection to help activate macrophages
What cytokine is secreted by T cells that recognize an Ag?
IL-2
What is clonal expansion a result of?
Result of cell proliferation and differentiation of the T cells into effector or memory cells.
True or False:
The effector CD4+ T cells respond to Ags by producing cytokines that have several actions, such as the recruitment and activation of leukocytes and activation of B cells.
True
How do effector CD8+ CTLs respond?
By killing infected and altered host cells.
List the phases of T cell responses.
> APCs display Ags and provide co-stimulation that guide T cell response.
> Ag recognition together with other activating stimuli induces several responses in T cells:
- secretion of cytokines - proliferation (clonal expansion) - differentiation into effector and memory cells
> Effector T cells are activated to perform functions that are responsible for the elimination of microbes andd, in disease states, for tissue damage.
> T cell responses decline after the Ag is eliminated.
> Generated memory T cells are long-lived cells with an enhanced ability to react against the Ags.
What are the 3 signals that are required for proliferation of T lymphocytes and their differentiation into effector and memory cells?
Signal 1 -> Ag recognition
Signal 2 -> Costimulation
Signal 3 -> Cytokines
What APCs can effector T cells recognize Ags from?
> macrophages
> B cells
What is always the first signal that ensures that the resultant immune response is Ag-specific?
Ag is always the FIRST SIGNAL.
Look over T-cell Receptor Signaling pathway.
Slide 11
What do superantigens bind to simultaneously?
- MHC class II molecules (not in the peptide-binding groove)
- V region of the beta subunit of the TCR
Are superantigens processed into peptides?
No
What do superantigens do to activate T cells?
They “glue” T cells to APC and activate the T cell.
Give an example of a bacterial superantigen.
Staphylococcal enterotoxins (SE) are bacterial superantigens that cause common food poisoning and the toxic shock syndrome toxin (TSST).
How can superantigens cause shock?
They “glue” T cells to APC and activate the T cell. Thus, causing T cells to produce massive amounts of cytokines which may lead to shock.
What does an Ag recognition (signal 1) without costimulation for T cells result in?
May make T cells unresponsive or anergic (tolerant).
What are the most powerful T cell mitogens ever discovered?
Superantigen (SAgs)
How do SAgs interact with T cells?
SAgs bind, as intact molecules to the class II MHC expressed on professional APCs outside the peptide-binding groove then sequentially bind the TCR via the variable region of the beta-chain.
Which pro-inflammatory cytokines are massively systemically released in response to SAgs and can lead to fever and shock?
- TNF-alpha
- IL-1 beta
- IL-2
True or False:
Resting DCs express few or no costimulatory molecules levels of which are not enough to activate naive T cells.
True
What provides signal 2 needed for T cell activation?
microbes and cytokines produced during innate immune responses (inflammation) activate APCs to express costimulators, such as B7 molecules, which provide signal 2.
What costimulatory molecules expressed on activated APCs bind to T cell surface receptor CD28?
> B7-1 (CD80)
> B7-2 (CD86)
Fill in the Blank:
CD28 signals work in _____ with Ag recognition to promote the survival, proliferation, and differentiation of the specific T cells.
cooperation
True or False:
The outcome of T cell activation is influenced by a BALANCE between engagement of activating and inhibitory receptors of the CD28 family.
True
What immune checkpoint is induced in naive T cells at the time of their initial response to Ag?
CTLA4-mediated immune checkpoint
Naive and memory T cells express high levels of what cell surface protein, and do not express what protein that is stored in intracellular vesicles?
Naive and memory T cells express high levels of cell surface CD28 but do not express CTLA4 which is stored in intracellular vesicles.
What causes the transport of CTLA4 to the cell surface?
TCR being triggered by Ag encounter.
What does CTLA4 function to do?
Functions as a signal dampener to maintain a consistent level of T cell activation.
True or False:
The stronger the stimulation through the TCR (and CD28), the greater the amount of CTLA4 that is deposited on the T cell surface.
True
What is the major role of the programmed cell death protein 1 (PD1)?
Regulate inflammatory responses in tissues by effector T cells recognizing Ag in peripheral tissues.
Fill in the Blank:
Activated T cells _____ _____ and continue to express it in tissues.
upregulate PD1
What signals induce the expression of PD1 ligands?
Inflammatory Signals
What control does PD1L regulate in the activity of T cells?
PD1L downregulate the activity of T cells and thus limit collateral tissue damage in response to a microorganism infection in that tissue.
The best characterized signals for PD1L induction is ______ cell-derived from Th1 cells.
IFN-gamma
What can excessive induction of PD1 on T cells in the setting of chronic antigen exposure do?
Can induce an exhausted or anergic state in T cells.
True or False:
PD-1 is a rheostat for immune responses.
True
What is the autocrine IL-2 a growth factor for?
> CD4+
> CD8+
Which two cell types does IL-2 potentiate cytotoxicity in?
> NK cells
> CD8+ T cells
What does IL-2 co-stimulate T cells to produce?
> IL-4
IL-5
IFN-gamma
Which cytokine promotes the development of regulatory T cells?
IL-2
Can IL-2 induce an autocrine activation-induced death in T cells?
Yes (see CTLA-4)
What anti-apoptotic protein is induced by IL-2?
Bcl-2
Which cytokine stimulates cell cycle progression by degradation of the cell cycle inhibitor p27?
IL-2
True or False:
IL-2 is required for the survival and function of Treg cells.
True
** NO other cytokine can replace IL-2 for the maintenance of functional Treg cells **
True or False:
IL-5 stimulates the survival, proliferation, and differentiation of Ag-activated T cells.
False - IL-2 does.
In vitro, which cytokine has been shown to simulate the proliferation and differentiation of NK cells and B cells?
IL-2
What is the function of newly-expressed CD69 on T cells?
retention in lymph node
What is the function of newly-expressed IL-2R alpha (CD25) on T cells?
proliferation
What is the function of newly-expressed CD40L on T cells?
Activation of DCs, Macrophages, and B cells
What is the function of newly-expressed CTLA-4 on T cells?
control of response
What is the result of CD69 binding to and reducing surface expression of the sphingosine 1-phophate receptor S1PR1 in T cell activation?
Activated T cells are RETAINED in the LNs long enough to receive the signalsthat initiate their proliferation and differentiation into effector and memory cells.
When does CD69 expression decrease on T cells?
after cell division
The re-expression to high levels of which receptor allows activated T cells (effector and memory cells) to exit the lymphoid organ?
S1PR1
The expression of which protein enables activated T cells to respond to growth-promoting IL-2?
CD25 (IL-2Ralpha)
What causes the expression of CD40L on activated T cells?
Ag recognition induces expression of CD40L on activated T cells (can be with or without B7 co-stimulators).
The expression of CD40L (CD154) is highly increased in ctivated T cells within how many hours after Ag recognition?
24 - 48 hours
** CTLA-4 (CD152) also increases within 24 - 48 hours after Ag recognition **
The expression of which ligand on activated T cells enables activated T cells to help DCs, macrophages, and B cells to become better APCs?
CD40L
True or False:
The CD40L engages CD40 on APCs and may stimulate the expression of more B7 molecules and the secretion of cytokines that activate T cells.
True
What does CTLA-4 do?
Functions as an inhibitor of T cell activation and thus as a regulator of the response.
What part of the T cell response is responsible for maintaining homeostasis in the immune system?
Decline of T cell response.
What happens as the level of co-stimulation and IL-2 decrease?
Levels of anti-apoptotic proteins in the cells drop.
What triggers the mitochondrial pathway of apoptosis in the decline of T cell response?
IL-2 Starvation
In addition to IL-2 starvation griggering the mitochondrial pathway of apoptosis, the addition of whay other regulatory mechanisms contribute to the normal contraction of immune responses?
> inhibitory receptors CTLA4 and PD-1
apoptosis induced by death receptors TNFRI and Fas
Treg cells
True or False:
Memory cells may develop from effector cells along a linear pathway, or effector and memroy populations follow divergent differentiation and are two alternative fates of lymphocytes activated by Ag.
True
In the development of memory T cells, what are the two outcomes according to the linear model of memory T cell differentiation?
> most effector cells die
> some survivors develop into the memory cells
In the development of memory T cells, what is the outcome according to the branched differentiation model?
Effector and memory cells are alternative fates of activated T cells.
In the response to Ag and costimulation, what do naive T cells differentiate into?
> effector T cells
> memory T cells
What cell type constitutes the most abundant lymphocyte population in the body for the majority of a person’s lifetime?
memory T cells
Where do the vast majority of memory T cells reside?
Tissue sites, including lymphoid tissues, intestines, lungs and skin.
What drives differentiation of effector cells in CD4+ T cells?
T-bet
What protein promotes the generation of memory T cells?
Blimp-1
What is responsible for the prolonged survival of memory T cells?
They express increased levels of anti-apoptotic proteins.
How quickly do memory T cells respond to Ags compared to naive T cells?
Naive T cells respond to Ag in 5 -7 days.
Memory T cells respond to Ag in 1 - 3 days.
True or False:
The number of memory T cells specific for any Ag is greater than the number of naive cells specific for the same Ag.
True
typically 10- to 100-fold more than the pool of naive cells
What does the maintenance of memory T cells depend on? Also, what does it not require that naive T cells do?
Dependent on -> cytokines
Does not require -> Ag presence
Which cytokines induce the expression of anti-apoptotic proteins and stimulate low-level proliferation in memory T cells?
IL-7
IL-15
True or False:
Memory cells are able to migrate to peripheral tissues and respond to Ag at the sites.
True
What are the 3 distinct phases that memory T cells pass through?
1) memory generation
2) memory homeostasis
3) immunosenescence
During which portion of a lifespan does memory T cells mostly generate following Ag exposure?
- during infancy
- during youth
- during young adulthood (0-20 years)
When do memory T cells typically show sensescent changes?
> 65 years
**memory T cell levels subsequently plateau and are maintained through homeostasis throughout audlthood (30-65 years), after which time they show senescent changes (age >65 years).
What are the 3 phenotypic markers for memory T cells?
- IL-7R
- CD45
- CD27 (function is unknown)
What are the two subsets that CD4+ and CD8+ memory T cells are divided into based on their homing properties and functions?
> CENTRAL memory T cells (Tcm cells) express the chemokine receptor CCR7 and L-selectin and home mainly to LNs, spleen and circulate in the blood.
- Proliferate (high production of IL-2) and generate many effector cells on Ag challenge.
> EFFECTOR memory T cells (Tem cells) circulate in the blood.
- DO NOT proliferate but produce IFN-gamma and TNF or become cytotoxic.
Do effector memory T cells (Tem cells) proliferate?
NO - but produce IFN-gamma and TNF or become cytotoxic.
What are resident tissue memory T cells (Trm cells) and what do they produce?
RESIDENT tissue memory T cells (Trm cells) reside in epithelial barrier tissues at the interface between the host and the environment.
- Trm cells produce IFN-gamma and TNF and are specific for pathogens and other Ags that have been encountered previously through that barrier epithelium.
Review Slide 44
role of Trm cells in tissue-specific autoimmune and inflammatory disease
