III - T cells Flashcards by ahmad elmowag

how do T cells recognise antigens

through their T cell receptors
(TCR)

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how does the TCR recognise an antigen

can only recognise an antigen if it is bound to a major histocompatibility complex molecule (MHC)

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what is the structure of the TCR

heterodimer composed of alpha and beta chains
each chain has 2 domains - 1 variable and one constant

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where does the TCR contact the antigen

complementary determining regions (CDR)

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how many CDR’s are there in the TCR variable region

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why are TCR’s so diverse

VDJ recombination

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what is step one of VDJ recombination

1 D region has to join to one J region

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what is step 2 of VDJ recombination

V region binds to the DJ region

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what is step 1 of recombination at the signal sequence

RAG protein complex binds to 12/23 bp spaced recombination signal sequence (RSS)

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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

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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

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what is step 4 of recombination at the signal sequence

other proteins bind to the hairpins and the cleaved RSS

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what is step 5 of recombination at the signal sequence

additional bases may be added or removed to generate imprecise ends

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what adds or removes bases in VDJ recombination

add - terminal deoxynucleotidyl transferase (TdT)
remove - exonuclease

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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

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where do segments join

at the most variable regions

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what do the segments correspond to

the CD3 loop of the TCR

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function of MHC molecules

bind to proteins from pathogens and present them to T cells
‘antigen presentation’

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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)

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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)

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what are the 3 types of APC’s

dendritic cells
activated macrophages
activated B cells

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what are the peptides that present MHC from

self proteins
viral/bacterial proteins
exogenous proteins

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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

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what is another function of CD4 and CD8 cells

co-receptors
bind MHC and help TCR signalling

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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