T Lymphocyte Activation Test II Flashcards
How are Ags transported to LN from periphery?
By mature activated DC’s
What two steps can occur after T cells are activated and differentiate into effector cells?
- Remain in lymphoid organs to help B lymphocytes
2. Migrate to sites of infection to help activate macrophages
What chemokine is secreted after Ag recognition by T cells, along with clonal expansion?
IL-2
How do effector CD8+ CTLs function?
By killing infected and altered host cells
What responses are induced by Ag recognition accompanied by co-stimulation in T cells?
Secretion of cytokines
Proliferation (Clonal exp.) IL-2 needed
Differentiation into effector and memory cells
What three signals are required for proliferation and differentiation of T cells?
Ag recognition
Costimuolation
Cytokines
What kind of signal does CD28:CTLA4 give?
Inhibitory-
What kind of signal does CD28:CD80/86 give?
costimulatory signal
What does CD2:CD48/59 do?
adhesion with APC’s
What does LFA1:ICAM1 do?
adhesion with APC’s
What is significant about Bacterial superantigens SAgs?
They are potent activators of T cells without co stimulatory signals. They are the exception to the fact that Ag recognition by TCR alone doesn’t stimulate clonal expansion of naive T cell.
How do SAgs work?
SAgs glue T cells to the APC’s for a prolonged amount of time activating T cells and inducing robust proliferation of SAgs activated T cells and produce massive amounts of IFN-y that activates Macro. to overproduce TNF and IL-1 which leads to shock.
Where do SAgs bind?
Simultaneously bind MHC class II molecules outside the peptide binding groove and V region of the beta subunit of the TCT
What happens to T cells if they recognize an Ag but without costimulation?
They may become anergic
What activates DC’s to express costimulators such as CD80/86 and what does that do?
Microbes and cytokines produced during innate response.
Provides costimulatory signal two making APC’s capable of activating naive t cells
Activated DC’s produce what cytokine and what is its role in costimulation of T cell activation?
IL-12 (signal 3) which stimulates differentiation of naive T cells into effector cells
Describe T cell costimulation by CD28?
It binds the costimulatory molecules B7-1 (CD80) and B7-2 (CD86) which are expressed on activated APC’s
How are T cell responses regulated?
The expression of B7 is regulated by CD28 inhibitory or activating proteins.
What type of cells express ligands such as B7 family?
APC’s
What type of cells express receptors such as CD28,CTLA-4, ICOS and PD-1?
T cells
Describe CD28?
Expressed constitutively on T cells.
Costimulation of naive T cells and generation of T reg cells is major function.
Binds with CD80/86 (B7-1 and B7-2)
Describe CTLA-4?
Expressed on T cells and inducible.
Function is negative regulation of immune responses, self tolerance.
Binds CD80/86 (B7-1 and B7-2)
ICOS?
Expressed on T cells and inducible.
Function is costimulation of effector and regulatory T cells. Generation of follicular helper T cells.
Binds with ICOS-L (CD275)
Describe PD-1?
Expressed on B cells, T cells, Myeloid cells and inducible.
Function is negative regulation of T cells
Binds with PD-L1 and PD-L2
Describe B7-1 and B7-2 (CD80/86)?
Expressed on DC’s macrophages and B cells
binds with CD28 and CTLA-4
ICOS-L (CD275)?
Expressed on DC’s macrophages B cells and others. Binds with ICOS
PD-L1 and PD-L2/
Expressed on B cells endothelial, epithelial and tumor cells
CTLA-4 checkpoint?
Induced in naive T cells at time of initial response to Ag. High surface levels of CD28 and CTLA-4 is stored intracellularly in vesicles. AFter TCR is triggered CTLA-4 is transported to cell surface, stronger/longer stimulation = greater amount of CTLA-4 on surface.
Functions as signal dampener to maintain consistent level of T cell activation
PD-1 checkpoint?
Major role is to regulate inflammatory respones in tissues by effector t cell recognition of Ag in tisssues. Activated T cells upregulate PD-1 and express it in tissues. Inflammatory signals induce expression of PD1 ligand which downregulates activity of T cells limiting collateral damage.
In the PD1 checkpoint what is the best characterized signbal for PDL1 induction?
IFN-y derived from Th1
How are Th1 cells generated?
IL-12 activates STAT4 which leads to expression of T-bet that facilitates Th1 expression
How are Th2 cells generated?
IL-4 activates STAT6 that leads to GATA3 expression that makes Th2.
How are Th17 generated?
IL-6 activates STAT3 that leads to expression of RORyt which makes Th17.
How are T reg cells generated?
TGF-B activates SMAD2-SMAD4 which promotes expression of FOXp3 and generates T reg.
What are the five biological actions of IL-2?
- Autocrine growth factor for CD4 and CD8 cells
- Potentiates cytotoxicty of NK cells and CD8 t cells
- Co-stimulates T cells to produce IL-4,5 and IFN-y
- Promotes dev of T reg cells
- Induces autocrine activation induced death in T cells
How does IL-2 stimulate survival proliferation and differentiation of Ag activated T cells?
Induces anti-apoptotic Bcl-2 protein and stimulates cell cycle progression by degrading P27 and inhibitor
Autoimmune disease arise as a failure of what type of cell?
T regulatory cells
What does CD69 do?
Retention of T cells in LN
How does CD69 expression change after T cell activation?
CD69 reduces S1PR1 which is needed to leave LN. Due to this the activated T cells are kept in the LN long enough to receive signals that initiate proliferation and differentiation into effector and mem cells. AFter cell division CD69 expression decreases and S1PR1 increases and they can leave LN.
Expression of CD25 (IL-2Ra) signifcance?
Expression only occurs in Ag activated T cells and an increase in expression enables t cells to respond to IL-2 by proliferation
What does the expression of CD40L on activated T cells do?
enables activated t cell to help DC’s, macro, and B cells become better APC’s. It engages CD40 on APC’s and stimulates expression of more B7 molecules and secretion of cytokines that activate T cells
IL-2 starvation?
Triggers mitochondrial intrinsic pathway of apoptosis
What contributes to the normal contraction of immune responses?
Inhibitory receptors CTLA4 and PD-1
Apoptosis induced by death receptors TNFRI and Fas
Inhibition by Treg cell products
How do cells differentiate into effector and memory cells?
In response to Ag and costimulation
What is the linear model of memory T cell differentiation?
Most effector cells die and some survivors develop into memory cells.
More likelly than branched differentiation
What is the branched differentiation model?
Effector and memory cells are alternative fates of activated T cells
What makes up the most abundant lymphocyte population in the body during the lifetime?
Memory T cells
Transcription Factor T-bet does what?
Drives differentiation of effector cells in CD4+ T cells
Transcription Factor Blimp-1 does what?
Promotes generation of memory cells
What are the subsets of CD4 and CD8 memory T cells?
Divided based on homing and functions.
Resident memory T cells (Trm Cells) found in epithelial barrier tissues. They produce IFN-y and TNF and are specific or pathogens that they previously encountered.
Central memory T cells (Tcm cells) express chemokine receptor CCR7 and L selectin and home to LN and spleen and circulate blood, upon re exposure to Ag they proliferate and generate effector cells.
Effector memory Tem cells circulate the blood, do not proliferate but produce IFN-y and TNF, when enter tissues can become Trm cells and stay in epithelium
Three properties of memory cells?
Ability to survive in quiescent state without Ag-produce anti-apoptotic proteins
Make larger and more enhanced responses than naive cells, 1-3 days not 5-7 days
Number of memory T cells specific for Ag is greater than number of naive T cells for same Ag
What three phases do memory T cells pass through?
Memory generation
Memory homeostasis (naive cells not produced anymore)
Immunosenescence
What are the mechanisms of immunosenescence?
Memory cells undergo age associated changes in composition, telomeres shorten resulting in apoptosis.
Naive T cells no longer produced IMMUNOSENESCENCE SLIDE FINISH
