Lecture 24: Naive, Effector, & Memory T Cells: Activation & Function Flashcards
what are the main functions of CD4+ T helper cells?
cytokine production, immune polarization
are naive T cells antigen experienced?
no
what is the lifespan of CD4+ naive helper T cells?
5-7 weeks
what is the lifespan of effector T cells (CD4 and CD8)?
3-4 days
what is the lifespan of CD8+ memory cells?
years
what is the ratio of CD4 to CD8 T cells in humans?
2 CD4 for every 1 CD8
90-95% of CD4 and CD8 T cells use ____ type TCRs
alpha beta
if activated, naive T cells undergo ____ to make many copies of themselves that act as effector cells
clonal expansion
what happens to effector T cells once an infection has died off?
the effector T cells also die off, but some of them can remain as memory cells
naive T cells have already commited to _____, but have not yet committed to _____
a CD4+ or CD8+ lineage; T helper subsets (CD4+)
naive T cells require 3 signals for activation, what are they?
- TCR/MHC peptide presentation
- co-stimulation between CD28 and CD80/86
- cytokines like IL-2
IL-2 has 3 different potency levels depending on ____
which receptor it binds to
what cytokine is critical to T cell proliferation?
IL-2
what level affinity IL-2 receptor is expressed by naive T cells?
intermediate affinity IL-2RyB
what is the structure of the high affinity IL-2 receptor?
IL-2RyBa
after activation, T cells upregulate their ____ chain to have a high affinity IL-2 receptor
alpha (CD25)
t/f T cells with the IL-2RyBa have a competitive advantage over naive T cells
t
what stage of T cells work to remove pathogen?
effector T cells
what T cells make up the effector T cells?
CD4+ T helper subsets (Th1, Th2, Th17, Tfh, peripheral T reg cells) and CD8+ cytotoxic T lymphocytes
effector T cells do not require ____ co-stimulation, although ____ binding to target cell ICAMs may provide co-stimulation
CD28; LFA-1
what branch of T cells is important for the protection from re-infection?
memory T cells
are memory T cells metabolically active?
no
the activation requirements of memory T cells are ____(more/less) stringent than those of naive T cells
less
memory T cells can be activated by ___ , ____ and ___ cells
macrophages, dendritic cells, B cells
naive T cells can only be activated by ____ cells
dendritic
memory T cells can be subdivided based on ____ and ___
differentiation potential and locations
what are 4 memory T cells subsets?
- T(scm): memory stem cells
- T(cm): central memory cells
- T(rm): resident memory cells
- T(em): effector memory
where are T(scm) memory T cells found?
lymphoid tissues
where are T(cm) memory T cells found?
circulation/lymphoid tissues
where are T9rm) memory T cells found?
tissues
where are T(em) memory T cells found?
circulation / tissues
naive, effector, and memory T cells express different ____ that affect their trafficking and function
surface markers
what is CCR7 and its function on T cells?
chemokine receptor that receives signal (CCL21. CCL19) to traffic to secondary lymphoid organs
CCR7 is found in high amounts on cells found in what organs?
lymphoid tissues (Tscm & Tcm)
what is the function of CD62L (L-selectin) on T cells?
lymphocytes extravasation through high endothelial venules
on what cells is CD62L (L-selectin) found?
cells found in lymphoid tissues (Tscm and Tcm)
CD44 is increased after ___
T cells activation
CD44 is found in low amounts on ___ T cells and high amounts on ___ T cells
naive; effector and memory
CD45RA is found in high amounts on ___ T cells and low in ___ T cells
naive, effector and Tscm; low on: Tcm, Tem, and Trm
Cd45RO is found in high amounts on ___ T cells and low amounts on ___ T cells
high: Tcm, Tem, Trm; low: naive, effector, and Tscm cells
what are CD45RA and CD45RO?
different isoforms of the same protein
what is the difference between CD45RA and CD45RO?
CD45RO is a more potent signalling molecule, so its upregulation permits faster, stronger signalling
which is used on cells that you want to make quickly (like Tcm, Tem, and Trm), CD45RA or CD45RO?
CD45RO
Fas is high on T cells that have been ____
activated
what is the function of Fas on T cells?
enable fratricide: induction of apoptosis in lymphocytes when they are no longer needed
do Tscm recirculate?
no
do Tscm produce cytokines?
no
what is the role of Tscm?
create other (more differential) memory T cells
what is the location of Tcm cells?
secondary lymphoid tissue and circulation
what cytokines are secreted by Tcm?
high IL-2 and not much else
what is the role of Tcm cells?
can differentiate into different effector subsets based on cytokine signals
what is the location of Tem cells?
circulation and peripheral tissues
what cytokines are released by Tem cells?
little IL-2 and many other cytokines
what is the location of Trm cells?
resident in tissues or original infection
MHC 1-restricted CD8+ T cells recognize and eliminate ___ cells
altered cells like cancer and virus-infected cells
t/f all nucleated cells express MHC 1, so T cells can inspect any MHC 1+ cell
t
what are the effector molecules of CD8+ T cells?
- membrane-bound Fas ligand
- secreted IFN and TNF (enhance immunity)
- secreted perforin and granzymes
what are the 3 stages of the CD8+ cell lifecycle?
- activation phase
- effector phase (killing pathogens)
- memory phase
dendritic cells must be ____ to be allowed to co-stimulate CD8+ T cells (this regulates the activation of cytotoxic T cells)
licensed
DCs present antigen to helper T cells on class __ MHC
2
helper T cells signal dendritic cells to upregulate ___ and ___ expression
cytokine and co-stimulatory
t/f DC licensing and CD8+ cell activation can be sequential or simultaneous
t
in what organs/locations does DC licensing and CD8+ activation occur?
in the lymph nodes or spleen
effector T cells upregulate high-affinity IL-2Ra (CD25) and produce IL-2, but not enough to support ____
autocrine growth and differentiation
what cytokine is needed for the expression of cytotoxic effector molecules (granzyme and perforin)?
IL-2
once antigen is eliminated, what happens to the IL-2 and CD8 cells?
IL-2 levels drop and CD8 cells begin apoptosis by fratricide and the left over memory CD8 cells
activated CD8+ T cells may develop into ____ cells or ___ cells
Tc1; Tc2
once CD8+ T cells differentiate into Tc1 cells, what is their function?
secrete IFN-y but not IL-4 and kill by perforin/granzymes and Fas
once CD8+ T cells differentiate into Tc2 cells, what is their function?
secrete IL-4 and IL-5, but only small amounts of IFN-y and kill primarily by perforin/granzymes
what are the primary cytokines secreted by Tc1 cells?
IFN-y
what is the preferred killing method of Tc1 cells?
perforin, granzymes, Fas ligand
what are the main cytokines secreted by Tc2?
IL-4 and IL-5
what is the preferred method of killing for Tc2?
perforin and granzymes
CD8+ cell mediated destrcution of target cells consists of what 4 steps?
- conjugate formation
- cytoplasmic rearrangement & membrane attack / death signal delivered
- CTL-target cell dissociation
- target cell destruction
in CD8+ killing of target cells, how long does it take for conjugate formation?
minutes
in CD8+ killing, conjugation formation involevs the formation of a ___ complex
supramolecular complex (SMAC)
in the congugation formation step of CD8+ killing, the CD8 cell bind to the foreign antigen and ____ stabilize the interaction between CTL and target cell
LFA-1 and LFA-3
in CD8 killig of target cells, during the conjugation formation step, TCR signalling causes a transient increase in avidity of ___ for ICAMS on the target cells that lasts ____ minutes
LFA-1; 5-10 min
in CD8 killing of a target cell, in the cytoplasmic rearrangement step, the ____ polarizes to the SMAC
centrosome/microtubule organizing center (MTOC)
in CD8 killing of a target cell, during the cytoplasmic rearrangement, ___ and ___ containing perforin and granzymes reorient in the cytoplasma and concentrate near the CTL and target cell interface
golgi stacks and storage granules
in CD8+ cell killing, the CD8 cells release granule contents into the space between the 2 cells by the process of ___
exocytosis
perforin monomers in the presence of Ca++ do what?
change in conformation and insert into the target cell membrane, then polymerize into pores that trigger endocyosis in response to membrane damage
in CD8 killing mechanism, granzyme binds to ___ on target cells and the resulting complex is ____
mannose-6-phosphate receptors; internalized into vesicles
____ allows granzyme B to be released from the vesicle into the cytoplasm where it cleaves substrates to initiate ____
perforin; apoptosis
how long after the CD8 cell dissociates from the target cell does death occur?
15 min to 3 hrs after
how do CD8 cells protect themselves from their own perforin and granzyme?
by expressing serpins (serine protease inhibitors) that inhibit granzyme B
t/f apoptosis is a quiet death where the cell components are recycled and intracellular contents are not released
t
the perforin/granzyme and Fas ligand cytoxic pathways depend on the sequential activation of ____
caspases
what are caspases?
cysteine proteases that cleave proteins after an aspartic acid residue
____ can directly cleave pro-caspase-3 and can also celave Bid
granzyme B
when granzyme B cleaves pro-caspase-3 and Bid, it induces release of ____ from mitochondria
cytochrome C
active caspase 9 cleaves ____
pro-caspase-3
caspase-3 activations leads to the activation of endonucleases that _____ and additional proteases that ____
frament target cell nuclear DNA; disassemble target cell cytoskeleton
what happens to viral DNA when a CD8 cell targets the cell containing viral DNA?
viral DNA is fragmented, preventing viral replication during the interval before cell destruction
how do CD4+ cells promote the development of CD8 memory cells?
release cytokines
are CD4+ cells required in the recall process of CD8+ memory cells?
no
t/f memory T cell responses typically reflect the same diversity as the primary response
t
activated memory T cells secrete enough ____ for proliferation and differentiation into effector CTL
IL-2
t/f it would be extremely rare to see a cell with BOTH CD45RA and CD45RO
t
what is the central SMAC vs peripheral SMAC?
where the interaction between target cell and T cell is happening; peripheral is where the interaction is stabilized by adhesion molecules
