BIOL 435 Ch. 8 p.1 (T-Cell Development) Flashcards
TCR structure
- variable and constant regions
- always membrane bound
- beta or delta chains = BCR H-chain
- alpha or gamma chains = BCR L-chains
TCR protein structure
- used monoclonal Ab to bond to specific parts of TCR to purify them
- heterodimer with an alpha and beta chain
early thmocyte development
-when first arrive, they aren’t T-cells
>can become NK cells, dendritic cells, B-cells and myeloid cells
*Notch (a receptor) commits them to the T-lineage
>GATA-3 TF becomes activated
steps in thymus
- Enter at CMJ: thymic settling precursors, DN1
- Cortex: DN2 (may become gamma-delta_
>*commitment to T-lineage - Subscapular cortex: DN3, rearrangment
- Cortex: DN4, alphabeta TCR DP, cell death or
- Through CMJ into medulla: CD4+ SP or CD8+ SP
DN2
-starts rearrangement
>beta, delta, gamma
*need both delta and gamma to be successful
*only need beta successful=more often
DN1 and DN2
-are mulipotent
>can give rise to myeloid and NK cells
T-cells that survive selection in thymus cortex
-migrate into medulla
+/- selection stages
-for a cell to become SP CD4+ or SP CD8+
if gamma delta succesful
-can leave the thymus
-0.5% of T-cells
-can secrete cytokines without Ag
-recognize lipids with unconventional MHC
*1st line of defense
>mucosa and skin
allelic exclusion
- not absolute
- may get 2 alpha chains
final screening in thymus
- removes autoreactive cells
- release into peripheral bloodstream
TCR rearrangement begins
-in the cortex and DN2 stage
stages of T-cell development
- CLPs leave bone marrow and enter thymus
- DN
- Gamma, beta, delta rearrangements occur simultaneously
- Display with pre-T-alpha=shuts down
- End of DN, pre-TCR expresses CD4 and CD8=DP
TCRbeta rearrangement
- 3x as likely
- first to take place and succeed
TCR gamma delta
-more common in fetal development
>environment may provide different signal cues
-most capable of secreting cytokines upon release from thymus
-less diverse
-1st response to pathogens and respond to cellular stress
TCR genes and rearrangement
-similar to Ig genes
-specific RSS
>some with 2D delta (12/23 rule)
>2D beta possible, but not observed
*D has a 12 and 23 on ‘either side’
if delta gamma successful
-TCR is tested and DN T-cell is release from thymus
if beta rearranges
- tested with a pre-Talpha (+ and - selection)
- if okay=alpha-chain rearrangment starts
CD3
- part of TCR complex
- has ITAMs
beta-selection
- DN thymocytes undergo it
- results in proliferation/differentiation
- than get DP
DP stage
- functional TCR alpha chain replaces surrogate
- positive/negative selection yields mature SP T-cell
CD4, CD8 DP thymocytes
-make up 80% of thymic cells
-undergo thymic selection
>in the cortex
postive selection
- selects thymocyes bearing receptors capable of binding self-MHC with low affinity=MHC restriction
- 2-5%
Death by neglect
- fail positive selection and fail to receive needed survivial signals
- 90-96%
- die by apoptosis
cTEC
- cortex thymic epithelial cells
- expres high leveles of MHC1 and MHC2 molecules
- developing T-cells ‘browse’ possible self peptide/MHC complexes
3 outcomes when encounter cTEC
- TCR can’t bind-die by neglect
- TCR binds too strong-negative selection
- TCR binds just right-positive selection (SP stage occurs)
