35 - B cells:Lymphocyte development Flashcards
Tolerance
ensures that immune system avoids destroying host tissue
how does self-reactive happen
Many of random rearrangement used to create B & T cell receptors could be
Tolerance helps to
keep self-reactive recognition molecules/cells from circulating in bloodstream
T cell development in Thymus
T cells develop initially in bone marrow= migrate t thymus to achieve full maturity
Developing T cells = thymocytes
-Undergo rigorous selection (to get tolerance)= mature naïve T cells
(So once they enter the bloodstream and then try to go through lymphocytes (lymph nodes) they are mature naive T cells)
Thymus:
Key anatomy& cell types
o Cortex & medulla
o Cortical epithelial cells
o Medullary epithelial cells
o Thymocytes
o Macrophages
o Cortical DCs
T cell precursors enter thymus as
double negative (DN) cells = don’t express CD4 or CD8 co receptors
CD4 & CD8 receptor expression changed during development in thymus
- Double negative (DN)
- Double positive (DP) – express on both CD4 & CD8
- Single positive (SP) – express either CD4 or CD8
During development, T cell develop… & undergo process to…
T cell develop MHC restriction & undergo process to ensure self-tolerance
what is Positive selection
Selects thymocytes bearing receptors capable of binding self-MHC molecules
-resulting in MHC restriction
o Deletion/positive selection to SP thymocytes
o Cortical epithelial cells involved
what is Negative selection
Select AGAINST thymocytes bearing high affinity receptors for self-MHC/self-peptide complexes
-Resulting in self-tolerance
o AIRE induce self-protein expression on thymic medullary epithelial cells
o Otherwise, clonal deletion
Sometimes arrest, anergy or editing
what happens in Positive selection?
HAPPEN in CORTEX:
Cortical epithelial cells – express high levels of MHC class I & II
-MHC molecules express self-peptides.
DP T cells can browse peptide MHC on surface of these cells & bind to them
If TCR can’t bind = cells die by neglect
-90-96% dies via apoptosis – why u need macrophage
If TCR bind too strongly = cells die
-Autoreactive cells
TCR bind low – just right = positive selection to SP stage occurs
-Specific to self-MHC but not specific to self-peptides
If binding occurs to MHC II with CD4 = T cell becomes
DP thymocyte becomes SP CD4+ T cell
If binding occurs to MHC I with CD8= T cell become
DP thymocyte becomes SP CD8+ T cell
what is AIRE
(autoimmune regulator)
can express peptides that can be may be found in other tissues outside of the thymus.
we can really test to make sure that these these SP thymocytes, if they do bind to any of these peptides, they’re autoreactive & deleted
Negative selection (central tolerance)
Negative selection = necessary to endure self-tolerance
Medullary epithelial cells – express TF called AIRE (autoimmune regulator)
-AIRE induce expression of many tissue-specific proteins in thymic epithelial cells
-Then processed & presented on MHC I or II
-Allow T cells to be screened against self-Ag safely in thymus
Cortical DCs
present self-peptides on MHC I or II
-Contribute to negative selection
-But happen in cortex
SP T cells can browse
self-p:MHC on surface of thymic epithelial cells and cortical DCs
Negative selection:
o If TCR don’t bind
o of TCR bind pMHC
If TCR don’t bind = cell survive
TCR bind = pMHC
-Clonal deletion: self-reactive T cells dies (most cases)
–Macrophages clean up debris
-Other options:
–Clonal anergy – autoreactive T cells inactivated
–Clonal editing – 2nd/3rd chances at rearranging a non-self-reactive TCR gene - to change specificty of TCR
Evidence of negative selection in cortex?
New findings can change how we think about the immune system & there is still so much we don’t know
Peripheral tolerance
T cell encounter pMHC without costimulation leading (anergy) & maintenance with Tregs
T reg - big role
Peripheral mechanisms of tolerance – also protect against autoreactive thymocyte
-Important for self-reactive T cell that escape negative selection in thymus
-Strong self-Ag signaling through TCR in absence of costimulation (signal 2) may drive T cells into anergy
-Regulatory T cells can help maintain peripheral tolerance
B cell development
B cell development being & mainly occur in bone marrow
-Completed in periphery (spleen)
Negative selection (Deletion) of autoreactive B cells:
-Proper gene rearrangement of H & L chain genes Ig that shows self-tolerance
Only negative selection required = no need for MHC restriction
Negative selection of B cells in bone marrow (central tolerance)
- BCRs tested against self-Ag: 3 possible outcomes
Clonal deletion of strongly autoreactive cells
-Apoptosis
Receptor editing – reactivation of recombination machinery
-By chance
Anergy – induction of unresponsiveness to further stimuli
-Even self-Ag stimuli
No known AIRE equivalent for B cell developemnt, so…
range of self-Ag available for B cell to test against is lower
Self-Ag for B cell
soluble proteins in circulation/presented on stromal cells & other cells
