T-cell 3: Receptor diversity and T-cell development Flashcards
Receptor diversity
- similar to immunoglobulin (antibody) light chain and heavy chain gene rearrangement (VDJ recombination)
TCR rearrangement
- alpha chain (V joins with J) - like the light chain
- beta chains (V, D, and J chains) - like the heavy chain
Diversity:
- -> which V and D and J
- -> which alpha and beta combine
TRECs (T-cell receptor excision circles)
- TRECs are segments of DNA that are excised during VDJ rearrangement in T-cells and B-cells
- TRECs remain in the T and B cells, but do not replicate and are diluted by cell division
- measured in newborn screening (detects severe combined immunodeficiency)
- low levels are bad - mean rearrangement is not happening a lot - we expect a lot in babies
Development of T-cells
- Progenitor T-cells migrate from the bone marrow to via blood to the thymus
- they mature in the thymus (T-cell = thymus dependent)
- from bone marrow to blood to venules in medulla of the thymus, to cortex of thymus
–> as individual grows older, thymus shrinks
In THYMUS:
- VDJ rearrangement
- Positive selection: t-cells that bind somewhat weakly to MHC
- Negative selection: t-cells that bind too strongly to self-antigens and self MHC will be removed
Migration to peripheral lymphoid organs - waits until it encounters foreign antigens and APCs.
Activated T-cells (differentiate into effector T-cells) - go to sites of infection or will remain in lymphoid tissue where they’re needed to help B-cells make their antibodies
CD3 - surface molecule on T-cells
- early on a T-cell will be double negative (no CD4, no CD8)
- then it displays both CD4 and CD8
- then it commits to having just CD4 or CD8 as it’s co-receptor with the T-cell receptor
- can use CD3 to measure t-cells in the blood (CD3 will tell you levels of all T-cells - as CD4 and CD8 are on and off)
Selection of T-cells
DN4 (double negative 4 stage): proliferation of t-cell
Double positive cells move deeper into thymic cortex
Have 3-4 days to be positively selected
Positive Selection
TCR must recognize corresponding self-peptide/self-MHC complex to be positively selected (not just the self-peptide) - must bind with some low affinity
At this stage, the t-cell commits to either CD4 or CD8
Thymic cortical epithelial cells: web of cell processes that make close contacts with double positive cells. They express the MHC molecules and self-peptides.
Negative Selection
- If the double positive thymocyte’s TCR binds too strongly to MHC/self-peptide complex, it dies by apoptosis
- Antigen presenting cells (dendritic cells and macrophages) are important in negative selection
- -> found in medulla of thymus
Affinity hypothesis
How does TCR binding to self-peptide/MHC complex result in 2 opposite outcomes?
1) low affinity binding –> survival
2) high affinity binding –> apoptosis