Lecture 11: Activation of T Lymphocytes Flashcards
Ag recognition by T cells induces what
Secretion of IL-2 which causes T cell proliferation
Three signals required for proliferation and differentiation of T lymphocytes into memory cells
Ag recognition (signal 1)
Costimulation (signal 2)
Cytokines (signal 3)
Activation of naïve T cells requires
Presentation of Ag by dendritic cell
CD28:CTLA4 complex on T cells is
Inhibitory signal
CD28:CD80/86 complex on T cell is
Activating signal
CD2:CD48/59 complex on T cell is
Adhesion with APCs
LFA1:ICAM1 complex on T cell is
Adhesion with APCs
Ag recognition without costimulation may cause
Formation of anergic or unresponsive T cells
Costimulatory molecule expression on unactivated DCs
Low levels of costimulatory molecules, not enough to activate naïve T cells
What stimulates the differentiation of naïve T c ells into effector cells, and it is released by what
IL-12 released by activated DCs
APCs express ___ while T cells express ____ (in the context of B7/CD28 complexes)
APCs express ligands while T cells express receptors
CTLA4 mediated immune checkpoint
Induced in Naïve T cells at the time of their initial response to Ag
Naïve and memory T cells express high levels of ____ but do not express ___
Naïve/memory T cells express high levels of CD28 but do not express CTLA4 which is stored in intracellular vesicles
When is CTLA4 expressed
After the TCR is triggered by Ag encounter- the stronger the stimulation, the greater the amount of CTLA4
CTLA4 functions as a
Signal dampener to maintain a consistent level of T cell activation
Major role of PD1
Not at the initial T cell activation stage
- Regulates inflammatory responses in tissues by effector T cells recognizing Ag in peripheral tissues
- Activated T cells upregulate PD1 and express it in tissues
PD1 ligand expression is induced by
Inflammatory signals in the tissues
PD1 Ligand function
Downregulate the activity of T cells and thus limit collateral damage in response to infection
What is the best characterized signal for PD1L induction
IFN-y released by Th1 cells
Excessive induction of PD1 on T cells (in setting of chronic Ag exposure) can induce
An exhausted or anergic state in T cells
Quick steps in generation of Th1 cells
IL-12 activates STAT4 which leads to expression of T-bet which facilitates generation of Th1 cells
Quick steps in generation of Th2 cells
IL-4 activates STAT6 that leads to expression of GATA-3 which facilitates generation of Th2 cells
Quick steps in generation of Treg cells
TGF-b activates SMAD2-SMAD4 which promotes the expression of FOXP3 and the generation of T regulatory cells
SAgs
Most powerful T cell mitogens ever discovered
Not processed into peptides
Simultaneously bind MHC II molecules (not in peptide binding groove) and the V region of the B-subunit of the TCR
SAgs induce
A robust proliferation of SAgs-activated T cells which produce massive amounts of pro-inflammatory cytokines TNF, IL-1 and IL-2 which may lead to shock
IL-2 costimulates T cells to produce
IL-4, IL-5 and IFN-y
How does IL-2 help reduce apoptosis and stimulate the cell cycle
Induces anti-apoptotic protein Bcl-2
Stimulates cell cycle progression by degradation of cell cycle inhibitor p27
IL-2 is required for the ____ and ____ of ____
Survival and function of Treg cells
Function of newly expressed CD69 on activated T cell
Retention in lymph node
Function of newly expressed IL-2R on activated T cell
Proliferation
Function of newly expressed CD40L on activated T cell
Activation of APCs
Function of newly expressed CTLA-4 on activated T cell
Control of response
CD69 function explained
CD69 associated and inhibits the function of S1P(1), inhibiting egress from LNs
CD69 binding reduces surface expression of S1PR1
Result of CD69 binding to activated T cell
T cell is retained in the LN long enough to receive signals that initiate proliferation and differentiation
CD69 expression decreases after cell division
Blood and lymph S1P extracellular concentration vs lymphoid organ S1P extracellular concentration
Blood/lymph S1P concentration is high, which causes down regulation of S1PR1. When it enters the lymph organ with low [S1P], it begins to re-express higher levels of S1PR1
CD40L expression is induced by
Ag recognition by T cell. Takes 24-48 hours
CD40:CD40L complex between T-cell/APC may stimulate
The expression of more B7 (CD28) molecules and the secretion of cytokines that activate T cells
As the level of costimulation and IL-2 decrease, what else decreases
The levels of anti-apoptotic proteins in the cell
What triggers the mitochondrial intrinsic pathway of apoptosis with respect to the decline of T cell responses
IL-2 starvation
What cells constitute the most abundant lymphocyte population in the body during lifetime
Memory T cells
Linear model of memory T cell differentiation
Most effector cells die, some survivors develop into memory cells
Majority of memory T cells reside where
In tissue sites- lymphoid tissues, intestines, lungs, skin
T-bet function in effector T cells
Drives differentiation of effector cells in CD4+ cells
Blimp-1 function
Promotes the generation of memory cells
Resident memory T cells (Trm)
Produce IFN-y and TNF and are specific for pathogens/Ags that have been encountered previously
Central memory T cells (Tcm)
Express chemockine CCR7 and L-selectin and home to LNs, spleen and circulate in blood
Effector memory T cells (Tem)
Circulate in the blood
Do not proliferate, but produce IFN-y and TNF or become cytotoxic
Upon entering tissue, Tem cells can become Trm cells and reside in epithelial barrier tissues
How do memory cells survive in quiescent state without Ag
They express increased levels of anti-apoptotic proteins
Memory T cell response compared to naïve T cell
Larger, faster, enhanced responses
Naïve cells take 5-7 days, memory cells take 1-3 days
There are more memory cells specific for a particular antigen than there are naïve cells
Maintenance of memory cells is dependent upon
Cytokines, but does not require Ag presence
What cytokines induce expression of anti-apoptotic proteins and stimulate low level proliferation
IL-7 and IL-15
Quick steps in generation of Th17 cells
IL-6 activates STAT3 the leads to expression of RORyt which facilitates generation of Th17 cells
