Lecture 14 - T Cell Selection

what components of T cell development is in the cortex?

- DN proliferate - DP cells - site of positive selection (cortical epithelial cells) - site of negative selection

what components of T cell development is in the medulla?

- SP thymocytes ---> ones ready to leave the thymus ---> specialized subset of T cells that are protecting the thymus (regulatory t cells)

When are RAG genes turned off in Thymocyte lineage commitment?

- after beta chain successfully rearranges - after alpha chain successfully rearranges - after gamma delta T cells rearrange

what happens if there are mutations in AIRE?

- autoimmune disease called APECED - systemic failure in immunological "self-tolerance"

what happens to T cells that have no or too high affinity for self-MHC?

- removed from the repertoire - die by apoptosis in the cortex

where do the self-peptides that are used in positive and negative selection come from?

- resident cells in thymus (epithelial/stromal cells - bone-marrow derived macrophages and DC in medulla and corticomedullary junction can travel to other tissues and pick up Ag - tissue specific Ag produced by subset of medullary epithelial cells

wjat are regulatory T cells?

- subset of CD4 TCRs that are autoreactive and block other T cells from becoming activated by self-antigens on the same APC

what is AIRE?

- transcriptional factor expressed by medullary epithelial cells - allows T cells to see "self antigens" in thymus to aid in negative selection

how are double-positive thymocytes positively selected?

CD4+8+ thymocytes will interact with thymic cortical epithelial cells that express both MHC 1 and 2 and present self-peptides. If the DP thymocyte has moderate or strong binding to the presented self-peptide, then it is selected to survive.

what T cells are negatively selected for?

DP thymocytes that have too high affinity with self-MHC

what transcription factor is required for regulatory T cell function?

FoxP3

what is allelic exclusion in T cells?

Once TCR beta chain successfully rearranges, it will stop further rearrangements. Proliferate, then start alpha chain rearrangements,

what is the mature T cell repertoire composed of?

TCRs that can interact with self-MHC with moderate affinity

what is the stochastic model of lineage commitment in DP T cells?

before any binding occurs with MHC on thymic cortical epithelial cells during positive selection, either CD4 or CD8 are randomly downregulated

what is the TCR repertoire?

collection of all TCRs in an individual

in the stochastic model, what happens to T cells that downregulate the wrong coreceptor?

die off

what distinguishes regulatory T cells from other CD4 T cells?

expression of CD25 receptor

which mechanism of lineage commitment in DP T cells is thought to be true?

instructive; CD4 and CD8 send different signals to the DP cells

what is central tolerance?

negative selection of autoreactive thymocytes

what is peripheral tolerance?

other mechanisms that act in the periphary

what is the purpose of negative selection?

prevent escape of autoreactive T cells

what is the instructive model of lineage commitment in DP T cells?

race to bind first; binding of CD4 to MHC2 provides a signal to downregulate CD8 and binding of CD8 to MHC1 causes CD4 to downregulate

what are the two models that explain lineage commitment of DP T cells to SP T cells?

stochastic and instructive

what interaction is required for generation of CD8+ T cells?

with MHC 1

what interaction is required for generation of CD4+ T cells?

with MHC 2