Lymphocyte Development

Where do B cells develop?

bone marrow

Where do T cells develop?

thymus

Which cells signal T and B cell differentiation?

stromal cells

How are TCR and BCR generated?

random genetic recombination

What signal from a stromal cell leads to B cell differentiation?

IL-7

What signal from a stromal cell leads to T cell differentiation?

notch signalling

What are the light and heavy chains made up of in B cells?

• light chains - V, J and C segments

• heavy chains - V, D and J segments

What are the different stages of B cell development (7)?

• stem cell

• early pro-B

• late pro-B

• large pre-B

• small pre-B

• immature B

• mature B

What happens during the early pro-B stage?

D and J segments of H chain begin rearranging

What happens in the late pro-B stage (3)?

• D and J rearranged

• V rearranges (in one allele) - completes H chain

• temporary L chain expressed to form pre-BCR

When is the first check of BCR development?

end of the pro-B stage

What happens during the first check of BCR development (3)?

• checks if H chain is functional

• if functional - moves onto large pre-B stage

• non-functional - second allele begins rearranging

Why is allelic exclusion important in immune receptor development?

decreases chance of auto-reactivity occurring

What is allelic exclusion?

successful arrangement of one allele blocks the other allele from rearranging

What happens if the first check of BCR development is successful (3)?

• second allele blocked from recombining (allelic exclusion)

• late pro-B cell receives signal via successful pre-BCR

• progresses to large pre-B stage and proliferates

What happens during the small pre-B stage (2)?

• V-J begin to rearrange in L chain

• BCR completely rearranged

When is the second check of BCR development?

end of small pre-B stage

What happens during the second check of BCR development (3)?

• checks new recombined BCR works

• if non functional - rearranges second allele

• if functional - blocks rearrangement of second allele (allelic exclusion)

What happens if the second check of BCR development is successful (2)?

• blocks second allele from rearranging (allelic exclusion)

• forms immature B cell with surface BCR (IgM)

When are B cells first checked for auto-reactivity?

as immature B cells (in the bone marrow - central tolerance)

What happens to autoreactive B cells (3)?

central tolerance - B cells are…

• edited

• deleted

• rendered anergic

Where do B cells complete maturation?

spleen

What happens during the B cell T1 maturation stage (3)?

• autoreactivity test

• if T1 B cells receive strong signal upon self-antigen encounter = deleted

• called peripheral tolerance

Where does the B cell T1 maturation stage take place?

spleen (peripheral tolerance)

How are T cells guided to the thymus?

follow chemokines through blood to corticomedullary junction in thymus

What segments are present in T cell alpha chains?

V, J and C

What segments are present in T cell beta chains?

V, D, J and C

What are the 2 different chains in a TCR?

alpha and beta

What leads to the variability seen in TCRs and BCRs?

random rearrangment

What is required for TCRs to signal?

CD3

What happens during beta selection during TCR development (4)?

• beta chain rearranges (and gamma and delta)

• pT alpha chain expressed and joins beta = pre-TCR

• pT alpha required for beta expression and association with CD3

• pre-TCR expression enough to signal (ligand binding not required)

What happens when a pre-TCR is successfully expressed and signals back to the T cell (5)?

• inhibits beta chain recombination

• pre-T cell proliferates

• induces alpha chain to rearrange

• CD4 and CD8 expressed

• pT alpha transcription stops

What is T cell positive selection?

selection of cells with functional TCR able to interact with self MHC-peptide complexes

Why is it important that TCRs can bind self-MHC molecules?

T cells only recognise peptides presented by MHC - if cannot bind MHC then cannot react to peptide

How is positive T cell selection carried out?

cortical thymus epithelial cells present peptides to double positive cells in both MHCI and MHCII

What are double positive T cells and where are they found?

• express both CD4 and CD8 - have not yet undergone lineage commitment

• only found in thymus

What is MHC restriction?

only cells able to respond to antigen from self MHCs are produced

What is determined during T cell positive selection (2)?

• MHC restriction

• lineage commitment

What is T cell lineage commitment?

become single positive T cells - express either CD4 or CD8 not both

What do CD4 single positive cells do (2)?

• recognise MHCII

• activate genes required for Th function

What do CD8 single positive cells do (2)?

• recognise MHCI

• activate genes required for CTL function

Which cells educate T cells?

thymus stromal cells

What is T cell negative selection?

deletion or modification of autoreactive CD4 and CD8 T cells in thymus

How is T cell negative selection carried out (3)?

• DC presents self antigen from blood/lymph

• mTECs present self antigen from tissues

• autoreactive T cells with high self-affinity deleted

What is an example of a mechanism of T cell central tolerance?

T cell negative selection in the thymus

What model is created by T cell negative selection (4)?

• affinity model of thymocyte selection

• low affinity binding = naive T cell

• intermediate binding = Treg cell

• high affinity binding = apoptosis