L9 T cell development Flashcards
what is the kd and affinity constant?
kd= dissociation constant
1/kd= affinity constant
kd for t cell: 10^-5
how do t cells change during development?
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.
how is tcr diversity generated compared to innate receptors?
T cell receptor: cd4 t cell with its co receptor and its signalling domains at the bottom.
Unlike innate receptors like tlrs which are germ-line receptors? : segments of genes on the tcr are encoded on different chromosomes and there are multiple copies of the gene segments. For the alpha chain there are over 100 different variable parts and over 50 joining (J) And for beta chain there are over multiple copies of the segments of genes that make up the tcr. This is how you get diversity of the tcr. (one of the reasons)
recombination events?
In the t cell early life within the thymus there is no tcr on the surface. Adds a receptor through recombination events, cutting and splicing gene segments together.
Beta chain done first then alpha chain follows.
TCR beta locus-germline
D to J rearrangement
V to dj rearrangement
Transcription
Mrna splicing
And it is a random process. Can get lots of different specificies. Happens again with the alpha chain. They pair together on the surface of a t cell to get a alpha beta tcr.
Lots of variation and generation of diversity.
allele exclusion?
Allele exclusion- require a functional alpha and beta chain on the surface of a t cell. If just a beta chain and it tries to pair with non functional alpha chain or a chain of a gamma delta tcr then the cell will die. Need functional pair.
embroynic thymus formation?
this is where the t cells actually develop. In the middle of the chest above the heart. During embryonic development: have endodermal and ectodermal cells that fuse together to form a thymic anlage. endoderm in the middle (medulla) and ectoderm (cortex) surrounding it, forming the stroma. Form a bilobed organ: the thymus.
No thymus= no t cells.
where is the thymus?
Where is the thymus?: older creatures like sea urchin only have innate immune receptors, no adaptive immune systems but have larger range of pattern recognition receptors.
In fish- thymus is the head/gill slit on both sides
Birds: in the neck
Mammals: between lungs above heart
thymus cortex and medulla?
Thymus:up in the cortex there are alot of epithelial cells with mhcs that are capable of presenting antigens to t cells called thymocytes (before they are developed into t cells). Can present antigens to the t cell once it has put tcr on the surface.
Medulla- more antigen presenting cells- dendritic cells + macrophages also capable of presenting antigens to thymocytes. Important for testing the t cell receptor for use/ danger?
chatgpt
Testing Process: The testing refers to the two stages of T cell selection:
Positive Selection (in the Cortex):
Thymocytes with TCRs capable of recognizing self-MHC molecules survive.
This ensures that T cells can interact with MHC molecules, which is crucial for their function in the immune response.
Negative Selection (in the Medulla):
Thymocytes are exposed to self-antigens presented by APCs (dendritic cells, macrophages, and medullary thymic epithelial cells).
If a thymocyte’s TCR binds too strongly to self-antigens, it is eliminated to prevent autoimmunity.
This ensures that T cells are not dangerous to the body.
Outcome of Testing:
Only thymocytes that can moderately bind self-MHC molecules without reacting strongly to self-antigens survive.
These cells mature into functional naive T cells and exit the thymus.
how does thymus function change with age?
Thymus function declines with age. Peak in teens and atrophies with age. Older people- smaller thymus. Weight is proportional to the number of t cells that can develop in it. Older people- do not make as many t cells everyday so more prone to infections etc.
thymic ontogeny?
T cell progenitors enter the thymus through high endothelial venules (in medulla/lower region) and migrate to sub capsular region where thymocytes start their maturation process through rearrangement of their tcr genes. As maturation proceeds and cells begin to express a specific receptor they move further into the thymic cortex. Interactions with tcr and mhc peptide complexes displayed by thymic cortex epithelial cells play a part in the fate of the thymocyte. At this point the deveopming thymocyte express both cd4 and cd8 and an alpha beta tcr. A cell that can recognise a mhc class 1 molecule will recieve a survival and maturation signal. Eventually the cell stops expressing cd4 and maintains expression of cd8. Thymocytes with a survival signal undergo positive selection. (same for mhc class 2). Thymocytes unable to recognise both do not receive a survival signal and undergo programmed cell death (apoptosis). Thymocytes that recognise mhc class 1 and 2 peptide complexes too strongly recieve a signal that drives them into cell death. In this way, thymocytes capable of recognising self peptide antigens are eliminated in negative selection of central tolerance. Surviving t cells migrate from the thymic cortex to the medulla. At this stage they remain capable of recognising self peptide antigens on other cells like macrophages and dendritic cells and undergo apoptosis. Remaining thymocytes- the naive cd4 and cd8 t cells pass out of the thymus and either return to the bloodstream directly passing into venules or via the lymphatic system.
what is the thymus and how is its structure divided?
T cell development takes place in the thymus- a specialised organ where t cell progenitors from the bone marrow migrate to and mature and differentiate.
The thymus is divided in several anatomical locations (top-bottom) subcapsular region, cortex, cortico-medullary junction, medulla. As thymocytes mature they pass from one environment to another.
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.
what does double positive mean?
Once it has the tcr on the surface it becomes double positive- expressing both cd4 and cd8 on the cell surface. Here the t cells are tested against mhc peptide on those various antigen presenting cells. If a signal from mhc class 2 it loses cd8 receptor and become a cd4 t cell and for mhc 1 opposite cd4 lost so becomes cd8, in double positive stage (check) proof that the mhc peptide complex determines the development/ maturity of developing t cell. This is how it acquires the mature phenotype
double negative?
Come in go deep down into cortex, arrive as dm1s (double negative 1) then double negative 2, double negative 3 and 4 where cutting and splicing is done to yield functional alpha/beta tcr. Random Cutting and splicing i.e the rag system (Recombinase activating gene) system of making alpha and beta chains- main way of generating diversity.
dm1- double-negative thymocytes that are still in the early phase of differentiation, before they start expressing any markers like CD4 or CD8
what happens if they recognise self or are useless?
f they see the affinity of mhc too much or if useless they will go through apoptosis. Therefore 95% of new thymocytes die.
Peptides recognised/presented are mhc and self antigen peptides In thymus. so if recognise self peptides too much, not released in the periphery as can cause autoimmune diseases.
