11. Activation of T lymphocytes Flashcards
what type of cells are constantly in the blood
naive T cells
what are the type of cells that can activate T cells
dendritic cells
where do naive T cells go from blood
2ndary lymph nodes where they meet dendritic cells
what is the movement from lymph nodes to organ they are needed
homing
how do activated T cells get to correct area
randomly go through circulation until it get to correct area
what helps to complete T cell differentiation
macrophages
what can effector T cells activate
Follicular B cells
how do Ag get to lymph nodes
mature/ activated Dendritic cells ingest and cleave Ag for presentation on membrane and take from periphery to lymph nodes
how do T cells find correct Ag
interact with many until find correct one
where do activated T cells go
remain in lymph nodes to help B lymphocytes or migrate to sites of infection to activate macrophages
what is induced by T cell recognizing Ag
IL2 secretion and clonal expansion
who do effector CD4+ T cells respond to Ags
produce cytokines
what do cytokines from activated CD4+ cells induce
recruitment and activation of leukocytes as well as activation of B cells
what is the function of CD8+ cell
kill infected or altered cells
what is activated by effector CD 4+ cells
macrophages, B cells and inflammation
what are the types of CD 4+ cells
effector and memory
CD 8 cells other name
cytotoxic T lymphocytes
what types of cells do naive CD 8 cells become
effector and memory CD8 cells
how does immune response work against intracellular pathogens
kill the host cell with macrophage ingestion then phagocytosis
how long does it take memory cells to differentiate
3-5 days so window opportunity due to innate immunity first
fever with no sickness is caused by
memory cells
what is induced when T cells have Ag recognition and co-stimulation
secrete cytokines, proliferation, differentiation into effector and memory cells
function of effector T cells
eliminate microbes and cause tissue damage
what happens after Ag is eliminated
T cell response declines
which T cells are long lived cells
memory
what is the advantage of memory T cells
enhanced ability to react against Ags
three signals for T cell activation
Ag recognition, costimulation, cytokines
naive T cells can only be activated by ___________ while effector can be activated by ________________
naive by DCs w/ antigen while Effector can recognize Ags presented by tissue macrophages and B cells
TCR activation by APC requires binding of which adhesion molecules
LFA1 to ICAM 1, CD2 to CD 48 or 59
inhibitory signal for TCR to APC
CTLA 4 to CD 80/86
what is CTLA 4
homology of CD 28
activation co-stimulation for signal 2
CD 28 to CD 80/86
what is LCK associated
CD 4 and 8
what dose LCK do once TCR is active
phosphorylates CD 3 and ZAP 70 after it binds P-CD3
what does ZAP 70 do
phosphorylates LAT and SLP76
what is the role of LAT
recruit GADS and GRB2
what is the role of GRB2
phosphorylates and activates PLCy
what does activated PLCy produce
IP3 and DAG
what does IP3 activate
NFAT and increased Ca2+ via calmodulin/ calneurin pathway
what does DAG lead to
activation of PKC to activate NFkB
besides Grab 2 and GADS, what does LAT activate
RAS and MAP K for AP!
what does LCK phosphorylate
ITAMS of CD3 complex
had do phosphorylated ITAMs cause
bring in ZAP 70 by SH2 domains to the P
what happens when ZAP 70 binds ITAM
Lck phosphorylates ZAP 70
what does phosphorylation of ZAP 70 cause
catalytic activity
what does ZAP-70 phosphorylate
LAT and SLP-76
what is the role of SLP 76
scaffolds to recruit other signaling molecules
what type of PTK is ZAP70
SYK
what do super antigens bind
MHC II molecules and V region of B TCR. Only specific TCRs
what is a saying for superantigens
glue T cells to APC and activate them
what is the problem of super antigens
activate many for massive amounts of cytokines for shock. KEEP T cells bound to MHC and don’t allow release
what can superantigens not do
be processed into peptides
example of bacterial superantigens
staphylococcal enterotoxins
what to staphylococcal enterotoxins cause
food poisoning and Toxic shock syndrome
what is the classification of super antigens
mitogens
concentration needed for SAg to cause fever, shock and death
less than 0.1 pg/ml
what makes SAg -T cell binding so bad
leads to proliferation of more SAg-T cells
what are the pro inflammtory cytokines that cause such problems with super antigens
TNF, IL 1 and IL2 for fever and shock
what type of immune response is T cell activation
innate immunity
what determines which helper T cells are activated
cytokines such as IL2
what activates APCs to produce costimulators
microbes and cytokines for innate immunity
what is an example of a costimulator besides CD 28/ CD 80/86
B7
which cytokines is signal 3
IL 12
what does IL 12 do
differentiation of naive T cells into effector cells
what are the anti-apoptotic molecules
Bcl Xl and BCL2
what is B7 another name for
CD 80
what is B7-2 another name for
CD 86
what is important for T cell costimulation
regulation of B7 and CD 80 co stimulators
how does CD 28 signals work
in cooperation with Ag recognition
are CD28 and B 7 the only co stimulators
no, many homologs exist and can be positive or negative selection
what influences the outcome of T cell activation
balance between activation and inhibitory receptors of CD 28 family
what is the goal of T cell activation
handle infection without causing tissue damage
what part of TCR activation do APCs express
ligands such as B7-1, B7-2, ICOS-L, PD-L1 and PD-L2
which TCR leads to inhibition of T cells
CTLA-4
what is ICOS
inducible T cell costimulator
what is the effect of ICOS
costimulate effector and T reg cells to generate ThF cells
homologs of PD-L1
B7-H1, CD 274
homologs of PD-L2
B7-DC, CD 273
what cells have PD-1 receptors
T cells, B cells, myeloid cells
what do PD or program death 1 do
negative regulation of T cells
what is CTLA 4 a signal for vs. PD1
CTLA is stay at this level of activation to not activate more while PD1 is for Apoptosis to complete end all T cell activation
what usually activates PD-1
tissue aggregation and inflammation
when is CTLA 4 induced and where
in naive T cells when Ag are initially sensed
how do CTLA4 get to surface of T cells
stored in intracellular vesicles that are transported to the surface with Ag encounter
what regulates CTLA 4 expression
greater TCR stimulation means greater CTLA 4
what acts as a signal damper and what does this mean
CTLA 4 for consistent T cell activation
what does PD1 checkpoint work on
effector T cells in peripheral tissue to regulate immune response in tissues
what causes PD1 expression
activated T cells
how are PD1 ligands expressed
inflammatory signals in tissue cause their expression
what does PD-1 do
downregulates activity of T cells to limit collateral damage
what is most common signal for PDL1
IFNy produced from Th1 cells
what does too much PDL1 lead to
exhausted or anergic state
what is a rheostat
controls T cell activation such as something that controls electrical current
how does PD1 inhibit TCR
SHP2 is activated to block ZAP70
what is 3rd signal shown with PD-1
IFNAR with JAK and TYK2
what do JAK and TYK2 induce
STAT 1 and 2 With IRF9 for cell growth and survival
what do cytokines control when T cells are activated
outcome of Ag recognition for effector T cell differentiation: which T cells produced
what does IL12 do
activates STAT4 for T bet production to cause Th1 cells
what activates Th2 cells and how
IL4 through STAT6 that leads to expression of GATA 3
what causes TH17 production
IL6 activates STAT3 which activates RORyt
what is RORyt
retinoic acid receptor related orphan receptor
what activates T reg cells
TGFB activates SMAD2 and 4 to activate FOX3 for Treg
what signal is cytokine production
signal 3
what is the first thing produced in CD4+ helper cells after T cell activation
C-Fox
when are IL2, CD 69, IL2Ra and CD40L produced on activated T helper cells
IL2 first at 12 hours, CD 69 at 1day, IL2Ra at 1 day, CD40L at 1.25 days
what is IL2R for
proliferation
what is CD 40 L for
activation of dc, macrophages and B cells
what is CD 69
keeps T cells in lymphoid organs by causing expression of S1PR1
what allows activated T cells to exit lymphoid organs
CD 69 expression decreases and S1PR1 is re-expressed for exit of effector and memory T cells
Cytokine for IL2Ra
CD 25
what is IL 2
autocrine growth factor for CD4+ and CD8+ T cells
which cells have cytotoxicity induced by IL2
NK cells and CD 8+ T cells
what does IL2 cause T cells to produce
IL4,5, and IFN y
what does IL2 promote the development of
regulatory T cells
how does IL2 cause death of T cells
induces autocrine activation induced death by CTLA 4
how does IL2 cause survival of T cells
induced antiapoptotic protein Bcl-2
how does IL2 induce proliferation
stimulates cell cycle progression by degrading cell cycle inhibitor p27
what is special about IL2
no cytokine can replace it
what T cell need IL2 for survival and function
Treg
which cells besides T cells have proliferation and differentiation stimulated by IL2
NK cells and B cells
what is S1PR1
sphingosine-1 phosphate receptor
why is CD 25 expression increased in activated T cells
binding of IL2 for proliferation
if IL2R doesn’t have an a subunit what occurs
IL2 binds but not enough affinity to surpass threshold
which ligand expressed on activated T cells
CD 40L
when is CD40L or CD154 expression increased
24 to 48 hours after TCR activation
what is the role of CD40L
helps DC, macrophages and B cells become better APCs by engaging CD 40 for more expression of B7 (CD80) and cytokines
CD 40L is a major inducer of
signal 3
what is clonal expansion
primary recognition of MHC complexes and causes many events
what does elimination of Ag lead to
contraction of T cell response
why does T cell response need to decline
maintain homeostasis
what drops with decline of T cell response
costimulation, IL2, and anti-apoptotic proteins
what does IL2 starvation cause
mitochondrial pathway of apoptosis
what induced apoptosis
death receptors TNFRI and FAS
what T cell causes contraction of T cell response
Treg Cells
how can Memory T cells develop
from effector cells or directly from naive T cells
linear model of memory t cells
most effector cells die and those that live become memory
Branched, differentiated memory t cells
effector and memory cells are alternative fates of activated T cells
how do memory t cells survive
anti-apoptotic proteins for whole life
what is the most abundant lymphocyte population in a person’s life time
memory T cells
where do memory T cells resides
tissue of lymphoids, intestines, lungs, skin for barrier of defense and where Ag first go
what influences the development of effector or memory T cells
TFs
Tbet drives
effector cells in CD4+ cells
BLIMP1 promotes
memory T cells
what is last immune response to develop in infants
T cell mediated immune response
why such a large memory T cell population
larger and enhanced response to Ags
time for naive T cells vs. memory T cells to respond to Ag
naive in 5 to 7 days while memory is 1 to 3 days
number of memory vs. naive for Ag
memory is 10 - 100x naive
where do Memory go for Ag
migrate to peripheral tissue to respond
what allows memory cell migration
adhesion molecules and chemokine receptors
what contributes to memory cell long life
slow self-renewing
what does maintenance of memory cells depend on
cytokines but not Ag
what induces the expression of Anti-apoptotic for low level proliferation of memory cells
IL7 and 15
3 phases of memory cells
generation, homeostasis and immunosenescence
when are memory cells made
infancy, youth, young adulthood (0-20)
when is homeostasis
plateau for 30-65 years old
what happens in immuno-senescence
after 65, memory cells stop production all together and pathogen susceptibility increases
markers of memory T cells
IL7R, CD 45, CD 27
how are CD 4+ and CD 8 memory T cells divided
subsets based on homing and fxn
central memory T cells
express chemokine receptor CCR7 and L selectins for homing in LN, spleen and blood
which type of memory T cells proliferate effector cells and how
central memory cells by high IL2 and make many effector cells
effector memory cells are found where
blood only
what do effector memory cells do
don’t proliferate but produce IFNy and TNF or become cytotoxic
whre are resident memory T cells
epithelial barrier tissues
what is produced by Trm
IFN and TNF for specific pathogens and other Ags encountered previously
