BIOL 435 Ch. 8 p.2 (T-Cell Development) Flashcards
mTEC
- medullary thymic epithelial cells
- strong=apoptosis
- strong to intermediate=T regulatory cell (T reg)
- weak=conventional T cell
MHC restriction
-ensured by positive selection
-TCR bind MHC=DP to SP
>if MHC1=CD8
>if MHC2=CD4
self tolerance
- ensured by negative selection (central tolerance)
- clonal deletion
clonal deletion
- induction of apoptosis in cells with too strong anti-self signalling/binding
- remains best proven and common method of tolerance induction in the thymus
do we delete all thymocytes reactive to tissue-specific Ag?
- no
- not all tissue types are in the thymus
- have the AIRE
AIRE
- autoimmune regulator protein
- induces expression of many specific-tissue proteins in medullary TECT
- binds epigenetic marks on histones to recruit TFs
- new T-cells can be screened against these Ag safely in the thymus
other methods of self-tolerance
- Clonal arrest
- Clonal anergy
- Clonal editing
clonal arrest
-autoreactive T-cells are prevented from maturing further
clonal anergy
-autoreactive T-cells are inactivated, but not deleted
clonal editing
-second or third chances at rearranging a non-self reactive TCR alpha-gene
instructive model
- TCR/CD4 and TCR/CD8 coengagement generate unique signals
- signals generated ‘instruct’ the T-cells which lineage to fullly commit to
stochastic model
- positively selected thymocytes randomly downregulated CD4 or CD8
- only cells with ‘correct’ co-receptor receive signals to continue development
- strength of signal and duration of signal from TCR/coreceptor
kinetic signalling model
-cells commit to CD4 lineage if they receive a continuous signal
-cells commit to CD8 lineage if stimulation signal is interupted
>IL-7 promotes CD8 differentiation
DP thymocytes commit to other lymphocytes
- NKT cells
- Intraepithelial lymphocytes (IELs)
- Regulatory T cells
* signal cues are unclear
NKT cells
- express a TCR with an invariant TCR alpha chain
- interact with CD1 molecules presenting lipid Ags
- bridge between innate and adaptive
IELs
- intraepithelial lymphocytes
- usually CD8+
- also have features of innate immune cells
regulatory T cells
-CD4+ subset
-helps to quench adaptive immunity
-less than 1%
>5-10% of CD4+ thymocytes
final maturation
- controlled by a cascade of events
- upregulation of Foxo1 TF
Foxo1 TF upregulates
- molecules required to help T-cells leave the thymus
- molecules giving survival signals
- a chemokine (sphinoshine 1-phosphate) receptor that helps cells exit and move to lymph nodes
recent thymic emmigrants (RTEs)
- T cells that have just exited the thymus
- not functionally mature yet
T regulatory negatively regulate immune responses
- belong to subset of CD4 T-cells
- expression of FoxP3 TF
- developmental cues are unclear
T-cells function to
- Deplete local area of stimulating cytokines
- Produce inhibitory cytokines
- Inhibit APC activity
- Directly kill T-cells (cytotoxicity)
B and T cell development similarities
- rearrangement of gene segments
- screening process to avoid self-reactivity
- production of small subsets with discrete function
- production of larger general purpose subsets
B and T cell development differences
-location of maturation and screening
-screen process used
>+ and - for T cells
>- for B cells
-specific arrangements and identities of gene segment recombination (ex. Ds)
-eventual outcomes of Ag receptor stimulatino
