dont know (2) Flashcards
T cells during gestation?
Gestation period: early on in embyro- gamma delta t cells/ cytokines dominate. After birth and during gestation they become very low in frequency as most become alpha beta t cells.
major stages in T cell development?
Major stages in t cell development; bone marrow- haemotopoetic stem cells that become the common lymphoid precursors that travel to the thymus. Go through double negative (DN) stages- are not expressing cd4 or cd8 on their cell surface. But express other molecules: cd44- hermes antigen binds to hyaluronic acid (a homing molecule) to help it migrate into the thymus from bone marrow. Cd25 (IL-2 receptor- a growth factor that drives t cell to proliferate)- do not have this on the surface.
Stage 2: have cd25 as t cell needs to divide. Large sized rapidly cycling cells.
Do not need to remember all details but remember cd44 and cd25 and interleukin 2 receptor.
L10- What are CTLs?
CD8 become CTLs where they are loaded with specialized cytolytic granules that contain
perforin and granzymes
Once effector CD8+ CTLs recognise their target cells in the periphery, a
“lytic immune synapse” is formed, and the cytolytic granules are secreted.
L10- CD8 lytic synapse?
a
after t cell proliferation and differentiated CD8 CTL cells formed in lymph node, they enter circulation and migrate to site of antigen where they form a lytic immune synapse.
Different from an initial immune synapse. to form the lytic synapse only need signal 1.
* TCR-
dependent
(signal 1)
BUT…
* costimulation
(signal 2) or
cytokines
(signal 3) NOT
REQUIRED
- cytotoxic lymphocytes that have been generated are very mobile, leave lymph nodes and survey the body to identify the target cell. The leading edge of a CTL is characterized by actin-rich
lamellipodia and the centrosome (microtubule-organizing center,
MTOC) is localized at the back of the CTL in the uropod. this allows them to rapidly migrate.
Stage 1. Initial interaction of CD8+ CTLs with target cells
* Initial interaction of CTL with a target cell is mediated by non-specific adhesion molecules – integrins: LFA-1
* In the absence of a specific TCR-recognised antigen the cells will
separate
LFA-1 (CD11a/CD18 ICAM-1 (CD54)
LFA-2 (CD2) LFA-3 (CD58)
Stage 2. Early events in CD8+ CTL lytic synapse formation
* Initial contact between the CTL and the target cell occurs through
actin-rich filopodia of the CTL that form an interdigitated contact sites (finger-like contacts) with the target cell.
* TCR–peptide–MHC interactions at the tips of the actin-rich interdigitations.
Step 3. Mature CD8+ CTL lytic immune synapse formation
* In the presence of a specific TCR-recognised antigen bound to class I
MHC cells and CD8 coreceptor engagement, CD8+ CTLs adhere strongly
and the formation of the lytic immune synapse is initiated, leading to
clustering of cytolytic granules towards the target cell.
T cell becomes polarised
- Centrosome/MTOC formation
- clustering of granules at point
of contact. centrosome contains the cytosolic molecules needed to kill the target cell.
Upon strong TCR engagement, the actin-rich lamellipodia move to the
periphery/edges of the lytic synapse leaving an actin-depleted area
(at 6 mins) the centrosome moves and docks at the plasma membrane, and cytotoxic
granules move along microtubules towards the lytic synapse.
➢ The docked centrosome marks the point at which lytic granules that contain cytotoxic
perforin and granzymes are secreted and consequently kill the infected or tumour target
cell by apoptosis
L10- what are stressed cells?
, NK cells are
selectively activated by
‘stressed’ cells’, which
upregulate activating ligands for
NK cells and thereby overcome
the inhibitory signaling delivered
by MHC class I molecules. This
is known as ‘stress-induced
self’ triggering of NK cell
activation.
L10- ITIM function?
Inhibitory receptors of NK cells
have immunoreceptor tyrosine-based
inhibition motifs (ITIMs), which engage
molecules that block the signalling pathways of
activating receptors.
ITIMs contain tyrosine residues that are
phosphorylated on ligand binding to the inhibitory
receptor and serve as docking sites for the
recruitment and activation of phosphatases, which
remove phosphates from several signalling
proteins or lipids generated by the signalling
downstream of NK activating receptors. The end
result is blocking of the signalling functions of
activating receptors
L10- what happens after the lytic synapse forms?
Together, these processes enable the delivery of cytolytic
granules to the lytic synapse, that leads to subsequent fusion of
lytic granules to the NK-cell membrane, which results in the
targeted release of their contents into the target cell
Because lytic granules exist in resting NK cells before activation, each
stage must be controlled to prevent accidental release of cytotoxic
mediators and to enable rapid directed secretion at the appropriate
moment.
L10- termination stage?
The crucial steps of the termination
stage are proposed to include a period
of inactivity and detachment
Down modulation of the
accumulated activating receptors
* NK-cell detachment from the target
cell
* Recycling of cytolytic capacity
L11- V segments?
Within v segments: framework regions making the physical immunoglobulin structures and within thema re CDRs- the unstructured loops at the ends and 2 of them are encoded by the v segments. Within 3rd cdr= formed by that junction of vdj being brought together.
Junction between VDJ sequence determines antigen specificity: the cd3 is important in determining what the final outcome is going to be.
L11- Why are recombination events unsuccessful?
The recombined exon must
maintain its codon reading frame to make a
functional protein.
* Random insertions and deletions will destroy the
triplet codon reading frame in 2 out of 3 cases.
* So only 1 out of 3 recombination events are
“Successful”.
