III - T cells Flashcards
how do T cells recognise antigens
through their T cell receptors
(TCR)
how does the TCR recognise an antigen
can only recognise an antigen if it is bound to a major histocompatibility complex molecule (MHC)
what is the structure of the TCR
heterodimer composed of alpha and beta chains
each chain has 2 domains - 1 variable and one constant
where does the TCR contact the antigen
complementary determining regions (CDR)
how many CDR’s are there in the TCR variable region
3
why are TCR’s so diverse
VDJ recombination
what is step one of VDJ recombination
1 D region has to join to one J region
what is step 2 of VDJ recombination
V region binds to the DJ region
what is step 1 of recombination at the signal sequence
RAG protein complex binds to 12/23 bp spaced recombination signal sequence (RSS)
what is step 2 of recombination at the signal sequence
the protein complex binds to each other
brings the segments closer to to be joined
what is step 3 of recombination at the signal sequence
DNA is cleaved to create hairpin structures at the end of the immunoglobulin gene segments
what is step 4 of recombination at the signal sequence
other proteins bind to the hairpins and the cleaved RSS
what is step 5 of recombination at the signal sequence
additional bases may be added or removed to generate imprecise ends
what adds or removes bases in VDJ recombination
add - terminal deoxynucleotidyl transferase (TdT)
remove - exonuclease
what is step 6 of recombination at the signal sequence
DNA ligase IV joins the ends of the gene segments to form the coding joint
and the RSS ends to form the signal joint
where do segments join
at the most variable regions
what do the segments correspond to
the CD3 loop of the TCR
function of MHC molecules
bind to proteins from pathogens and present them to T cells
‘antigen presentation’
features of MHC class I
found on most nucleated cells
present endogenous antigens
display self/viral proteins and intracellular pathogens
presents antigens to cytotoxic T cells (CD8)
features of MHC class II
found mostly on professional antigen presenting cells (APC)
presents exogenous antigens
phagocytosis, receptor mediated endocytosis
present antigens to helper T cells (CD4)
what are the 3 types of APC’s
dendritic cells
activated macrophages
activated B cells
what are the peptides that present MHC from
self proteins
viral/bacterial proteins
exogenous proteins
what happens if a new TCR recognises an antigen presented by MHC I or ag-MHC II
MHC I - loses CD4
ag-MHC II - loses CD8
what is another function of CD4 and CD8 cells
co-receptors
bind MHC and help TCR signalling
what occurs if there is recognition of self-antigen
thymocyte dies
what are the 4 main stages of T cell activation
initial interaction - with an APC
early co-stimulation
antigen recognition
late co-stimulation
what is step 1 of initial interaction
initial interaction is made with CD8 and target cells via non-specific adhesion molecules
during initial interaction, what occur if there is no antigen specific reaction
the cells seperate
what is step 2 of initial interaction
antigen specific interaction:
stable pairing and focused release of effector molecules
what is the final outcome of initial interaction
death of the target cell and release of CD8
what is the T cell synapse
close targeted interaction between a T cell and an APC
what is SMAC ( supramolecular activation cluster)
cell machinery re-arranges to point all molecules involved in cell activation to one place
what is the purpose of SMAC
allows targeted release of cytokines/granule contents
targeted interaction of MHC and CD3
local increase in co-stimulation molecules
what is early co-stimulation
provides essential extra signals to allow for T cell activation
prevents anergy
what is the purpose of early co-stimulation
prevents a T cell response to foreign antigens that don’t require it - a banana
done by employing an extra co-stimulation requirement for T cell activation
basically T cells will only switch on if there is inflammation happening
what are the most important early co-stimulation molecules
CD28
ICOS
what do CD28 and ICOS bind
CD80/CD86
ICOSL
what are CD80/86
CD80 is a constitutive - can be increased
CD86 is expressed on APC’s in response to inflammation
what does CD80 and CD86 trigger and how
trigger CD28 via mTOR
what does a triggered CD28 cause
enhances IL-2 transcription
what is IL-2
the key cytokine needed for T cell proliferation and survival
what do APC’s employ that acts as an extra check on T cells
they only express co-stimulation in the presence of inflammation
what does late co-stimulation occur through
the TNF receptor superfamily
what are the TNF superfamily members included in late co-stimulation
OX40
4-1BB
LIGHT
TRAIL
CD40
RANK
where does late co-stimulation occur
lymph nodes
T cells move in via afferent vessels into the lymph nodes
function of migratory dendritic cells
collect antigens from cells killed by an infection
process and present the antigen as peptides on MHC I
where do migratory dendritic cells move to and via what
move into the T cell zones of the local draining lymph nodes
through the HEVS and lymphatics
what happens if T cells see the antigen on the migratory dendritic cells
they lock onto the dendritic cells for up to 20 hours as T cell signalling occurs
T cell clones proliferate and receive co-stimulatory signals
after 72 hours where do T cells move from the lymph node
move to the tissue to carry out their effector function
they receive other signals at the sight of infection to fine tune their response
what is CTLA4 and where does it move to
major negative regulator
initially intracellular - moves to cell surface after TCR signalling
how does CTLA4 inhibit CD28 signalling
has a higher affinity for CD80/86 than CD28
CTLA4 binds all the CD80/86
what do naiive T cells express and why
IL-7 receptors
IL-7 is an essential survival factor
function of CCR7
allows naiive T cells to move in and out of lymph nodes
function of CD62L
allows naiive T cells to bind high endothelial venules in nodes
function of Th1 cells
key in developing immune response towards intracellular pathogens
what do Th1 cells release and what are they
IFN-γ
key pro-inflammatory cytokine
what does IFN-γ activate
activates macrophages and dendritic cells to produce reactive oxygen species to kill intracellular pathogens
what is Th1 transcription triggered by
APC producing lots of IL-12
what is the master transcription factor for Th1
T-bet
function of Th2 cells
key for defence against extracellular pathogens
help activate and maintain antibody response
how do Th2 carry out their role
produce large amounts of cytokines
activates mast cells, eosinophils and B cells
what do Th2 cells induce and help
induce mucus production
helps B cells class-switch into IgE
what can turn off Th1 cells
cytokines produced by Th2
what is Th2 differentiation triggered by
APC cells producing IL-4
what is the master transcription factor for Th2
GATA3
function of Th17
key in anti-fungal response
why are Th17 cells key drivers in almost all autoimmune diseases
they release powerful pro-inflammatory cytokines
IL-17
what are Th17 cells induced by
APC’s producing IL-6 and TGF-β
what is the key transcription factor for Th17
RORγt
function of Treg (regulatory) cells
supress self-reactive T cells that escape negative selection
how can Treg cells perform their function
inhibiting cytokines
cytolysis
metabolic disruption
targeting DC’s
where do memory T cells live
bone marrow
tissue like lungs
blood
