55-T Cell Development Flashcards
differentiation of t cells
occurs in thymus
production of common lymphoid progenitor cell
bone marrow
migrate to thymus
thymus
found above heart
increase in size until puberty and then replaced by fat tissue
Di George’s syndrome
have no thymus defects in number of mature t cells chromosome 22 severe immunodeficiencies CATCH-22
CATCH-22
Di George's syndrome cardiac abnormality abnormal facial structures Thymus aplasia cleft palate hypocalcemia/hypoparathyroidism on chromosome 22
thymocytes
immature t cell present in thymujs
checkpoints for maturation of t cells
notch signalling for lineage fate
rearrangement of TCR chains
positive and negative selection
selection of Cd4 or 8
expression of surface proteins can differentiate individual stages
using CD4 and CD8
double negative-most immature, no CD4 or 8
double positive-middle, both CD4 and 8
single positive- most mature, only 1 CD4 or 8
Notch1
first checkpoint
critical in determining T cell lineage
Notch1 ligands
on thymus
loss of Notch
B cells developed in thymus
gain of notch function
t cells in bone marrow
TCR structure
alpha and beta chains
transmembrane domain and constant and variable extracellular region
CD3 d, e, y, TCR z
drive intracellular signaling
antigen bound MHC
activated TCR
variable regions of TCR formed by what
somatic recombination
TCR alpha chain recombination
multiple copies of V and J, 1 copy of constant combined to form 1 V, J, C
TCR beta chain recombination
multiple V, D, J, and 2 constant combined to form 1 V, D, J, C
12/23 rules
recombination signal sequences spaced by 23 base pairs on 3’ end and 12 base pairs on 5’ end
RAG 1 and 2
recognize RSS (recombinational signal sequence) and cleave RSS to form closed hairpin loop
coding joint
region of DNA that will encode functional gene
signal joint
intervening DNA sequence that is removed by somatic recombination
Ku70/80 recruit DNA ligase to ligate ends
coding joint recombination
RSS brought together
RAG1 and 2 generates hairpin loop
Ku70/80 recruits DNA-PK and artemis to open hairpin loop
Ku70/80 releases DNA-PK and artemis and recruits TdT to fill in nucleotides
combinatorial diversity
random recombination of VDJ
junctional diversity
random addition of nucleotides during VJD recombination
rearrangement of TCR B chain
occurs first, can only occur once on one allele
rearrangement of TCR A chain
occurs second, can occur multiple times on both alleles, but only one is expressed
continues to rearrange until functional chain is produced or until it runs out of V and J regions-apoptosis
pre TCR A chain
associates with rearranged TCR B chain
mediates intracellular signaling pathways, proliferation of immature thymocytes, expression of CD4 and CD8, rearrangement of TCR a locus
2 T cell subtypes
alpha/beta
delta/gamma
once one is expressed the other goes away- mutually exclusive
what is TCR tested for after production
functionality and self reactivity
non functional TCR
die by death by neglect
Don’t react with MHC
self reactive TCR
die by negative selection, react with self antigens
positive selection
TCRs that are functional and non self reactive, only 2%
fate of double positive T cells- lineage choice
down regulate CD8
competent signalling differentiate into CD4
non competent signaling downregulate CD4 and become CD8
Defects in TCR a and b
lack of mature T cells
mutation in intracellular signaling molecules
lack of mature T cells
immunosuppressed
die within 1 year
T cell acute lymphoblastic leukemia
cancer cells from thymocytes
common childhood leukemia
T cell lymphomas
from mature peripheral T cells
found in older patients
