Activation of T lymphocytes Flashcards
Naive T lymphocytes recirculate through what?
LNs
Activation of naive T cells occurs in LNs if what?
They encounter TCR-specific Ags
Ags are transported to LNs from the periphery by what?
Mature (activated) DCs
Naive T cells transiently interact with many DCs and stop when?
They find specific Ag for TCR
T cells are activated to differentiate into effector cells that are located where?
remain in the lympoid organs to help B lymphocytes
migrate to sites of infection to help activate macrophages
Ag recognition by T cells induces what?
IL-2 secretion, clonal expansion as a result of cell proliferation, and differentiation of the T cells into effector or memory cells
The effector CD4 T cells respond to Ags by producing what?
Cytokines that have several actions, such as the recruitment and activation of leukocytes and activation of B cells
How do the effector CD8 CTLs respond?
By killing infected and altered cells
APCs display Ags and provide co-stimulation that guide what?
T cell response
Ag recognition together with other activating stimuli induces several responses in T cells including:
Secretion of cytokines
Proliferation (clonal expansion)
Differentiation into effector and memory cells
Effector T cells are activated to perform functions that are responsible for what?
The elimination of microbes and, in disease states, for tissue damage
T cell responses decline after what?
Ag is eliminated
What are long-lived cells with an enhanced ability to react against the Ags?
Memory T cells
The proliferation of T lymphocytes and their differentiation into effector and memory cells require what three signals?
Signal 1 - Ag recognition
Signal 2 - Costimulation
Signal 3 - Cytokines
What is always the first signal that ensures that the resultant immune response is Ag-specific?
Ag
What does activation of naive T cells require?
Recognition of Ag presented by DCs
Effector T cells can recognize Ags presented by what?
Tissue Mo and B cells
LCK (SRC PTKs) is activated in T cell receptor signaling, this results in what?
Phosphorylation of CD3 and activation of ZAP70 (SYK PTK)
What does activated ZAP70 phosphorylate?
LAT and SLP76
What does LAT recruit?
GRB2, GADS and phospholipase CI (PLC1)
What does the activation of PLC1 result in?
The production of inositol 3, 4, 5 - triphosphate (IP3) and diacylglycerol (DAG)
What does IP3 production lead to?
Increases of cytosolic free Ca2+
What can DAG activate?
Both protein kinase C (PKC)
What does LAT activate?
Ras and MAPK
What do superantigens bind simultaneously?
MHC class II molecules (not in the peptide-binding groove) and the V region of the β subunit of the TCR
They “glue” T cells to APC and activate the T cell
Superantigens are not processed into what?
Not into peptides but are able to bind to a specific family of TCR
What do T cells produce when activated by superantigens?
Produce massive amounts of cytokines which might lead to shock
What cause common food poisoning and the toxic shock syndrome toxin (TSST)
Staphylococcal enterotoxins (SE) - bacterial superantigens
Resting DC expresses few or no costimulatory molecule levels which are not enough to do what?
Activate naive T cells
Ag recognition (signal 1) without costimulation may make T cells what?
unresponsive or anergic (tolerant)
Microbes and cytokines produced during innate immune responses (inflammation) activate APCs to do what?
Express costimulators, such as B7 molecules, which provide signal 2
The APCs presenting microbial Ags providing signal 2 are now capable of activating what?
Naive T cells
What do activated APCs produce that can stimulate the differentiation of naive T cells into effector cells?
Cytokines such as IL-12 (signal 3)
What does the best characterized costimulatory pathway in T cell activation involve?
The T cell surface receptor CD28, which binds the costimulatory molecules B7-1 (CD80) and B7-2 (CD86) expressed on activated APCs
The expression of B7 costimulators is regulated and ensures what?
That T lymphocyte responses are initiated only when needed
CD28 signals work in cooperation with antigen recognition to promote what?
The survival, proliferation, and differentiation of the specific T cells
Numerous receptors homologous to CD28 and their ligands homologous to B7 have been identified. These proteins regulate what?
T cell responses both positively and negatively
What can the CD28 co-stimulatory receptor can be ligated by what?
CD80, CD86, and ICOS-L
The CTLA-4 (cytotoxic T-lymphocyte protein 4) co-inhibitor competes with CD28 for binding to what?
CD80 and CD86
What can CD80 also bind to and deliver a co-inhibitory signal?
PD-L1 (programmed cell death 1 ligand)
What does ICOS (inducible T-cell co-stimulator) compete with?
With CD28 for binding to ICOS-L?
What are naive T cells activated by?
Peptide-MHC complexes on activated APCs
What does Ag recognition induce?
The expression of CD40 ligand (CD40L) on the activated T cells
What does CD40L engage on APCs?
CD40
CD40L engages CD40 on APCs and may stimulate the expression of what?
More B7 molecules and the secretion of cytokines that activate T cells
What is used to bind to and block B7 molecules?
A fusion protein of the extracellular portion of CTLA-4 and the Fc tail of an IgG molecule is used
This prevents their interaction with the activating receptor CD28 and inhibiting T cell activation
What binds to and reduces surface expression of the sphingosine 1-phosphate receptor S1PR1?
CD69
CD69 binding to S1PR1 results in what?
Activated T cells retained in lymphoid organs long enough to receive the signals that initiate their proliferation and differentiation into effector and memory cells
After T cell division of activated T cells, what expression decreases?
CD69
The activated T cells re-express high levels of S1PR1 and therefore do what?
Effector and memory cells can exit the lymphoid organs
Describe expression of CD25 (IL-2Rα) after T cell activation
increased and enables activated T cells to respond to the growth-promoting IL-2
Describe expression of CD40L (CD154) after T cell activation?
Expression is highly increased in activaated T cells within 24 to 48 hours after antigen recognition
What does the expression of CD40L enables?
Activated T cells to help macrophages and B cells
CD40L on the T cells activates what?
Dendritic cells to become better APCs, thus providing a positive feedback mechanism for amplifying T cell responses
Describe expression of CTLA-4 (CD152) after T cell activation
The expression increases within 24 to 48 hours after Ag recognition
What does CTLA-4 function as an inhibitor for?
T cell activation and thus as a regulator of the response
IL-2 is an autocrine growth factor for what cells?
CD4 and CD8 T cells
What does IL-2 potentiates?
cytotoxicity of NK cells and CD8 T cells
What does IL-2 co-stimulates?
T cells to produce IL-4, IL-5, and IFN-gamma
What does IL-2 promote?
The development of regulatory T cells
What does IL-2 induce?
An autocrine activation-induced death in T cells
IL-2 stimulates the survival, proliferation, and differentiation of what cells?
Antigen-activated T cells
IL-2 induces what anti-apoptotic protein?
Bcl-2
What stimulates cell cycle progression by degradation of the cell cycle inhibitory p27?
IL-2
What is required for the survival and function of regulatory T cells ?
IL-2
Knockout mice lacking what have defects in regulatory T cells?
IL-2 or IL-2R
No other cytokine can replace ____ for the maintenance of functional regulatory T cells.
IL-2
What has also been shows to stimulate the proliferation and differentiation of NK cells and B cells in vitro?
L-2
Memory cells may develop from effector cells along a linear pathway, or effector and memory populations that follow what?
Divergent differentiation and are two alternative fates of lymphocyes activated by Ag
In response to Ag and costimulation, naive T cells differentiate into what?
effector and memory cells
According to the linear model of memory T cell differentiation, what happens to most effector cells?
They die and some survivors develop into the memory population
According to the branched differentiation model, effector and memory cells are what?
alternative fates of activated T cells
T cell-mediated immune responses to an Ags usually results in the generation of memory T cells specific for that Ag, this may persist for how long?
Years and even a lifetime
The types of transcription factors that are induced during T cell activation may influence what?
The fate between the development of effector or memory cells, the mechanisms are unclear
What drives differentiation towards development of effector cells in CD4 T cells?
T-bet
What promotes the generation of memory cells?
Blimp-1
Memory cells have the ability to survive in a quiescent state without what?
Ag
What do memory cells express?
Increased levels of anti-apoptotic proteins, which may be responsible for their prolonged survival
What can memory cells do better than naive cells?
Mount larger and enhanced responses
Naive T cells respond to Ag in how many days?
5 to 7
Memory cells respond to At in how many days?
1 to 3 days
The number of memory T cells specific for any Ag is (lesser/greater) than the number of naive cells specific for the same Ag
greater
typically 10- to 1—fold more than the pool of naive cells
Memory cells are able to migrate where? What do they express?
To peripheral tissues and respond to Ag at the sites
The expression of different adhesion molecules and chemokine receptors
What may contribute the the long life span of the memory pool?
Memory cells undergo slow self-renewing
What is the maintenance of memory cells is dependent on what?
cytokines but does not require Ag presence
What induces the expression of anti-apoptotic proteins and stimulate low-level proliferation of memory cells?
IL-7 and IL-15
What are the phenotypic markers for memory T cells?
IL-7R, CD45 and CD27 (function unknown)
What are CD4 and CD8 memory T cells subdivided into?
Subsets based on their homing properties and functions
Central memory T cells express what chemokine recepetor, selectin, and where does it mainly home?
CCR7 and L-selection and home mainly to LNs
What do effector memory T cells home to?
mucosal tissues
Effector memory T cells do not proliferate but produce what?
Cytokines IFN-γ or become cytotoxic
Elimination of Ag leads to what?
contraction of the T cell response
What is the decline of T cell response responsible for?
Maintaining homeostasis in the immune system
As the level of costimulation and IL-2 decrease, what happens to the levels of anti-apoptotic proteins in the cells?
It drops
IL-2 starvation triggers what?
The mitochondrial pathway of apoptosis
What various regulatory mechanisms contribute to the normal contraction of immune responses?
Inhibitory receptors CTLA-4 and PD-1
Apoptosis induced by death receptors TNFRI and Fas
Regualtory T cells
