T-cell development

What are the two interaction points that are needed for TCR recognition?

• Interaction between the TCR and antigen

• Interaction between TCR and MHC molecule

What determines the diversity in HLA molecules?

• genetics

• we can express upto 12 HLA molecules (x3MHCI and x3MHCII from both mother and father)

What is promiscuous binding specificity?

Where do T-cells originate and where do they develop?

• originate from bone marrow and develop in thymus via blood circulation

What happens to thymus quality with age?

A year after birth T cell development in the thymus slowly decreases

How do cells prepare for positive selection?

Step 1 in cortex of thymus → positive Selection for binding of TCR To Self MHC

• T cell precursors enter the thymic medulla via the blood and move into cortex for positive selection

• During positive Selection T cells gain expression of the TCR which is checked for functionality: (before positive selection)

  • first checkpoint is for functional Beta chain → if no 4 attempts before apoptosis if yes → continue

  • second checkpoint for functional alpha chain → if no rearrange until exhaustion, if yes → continue to selection

Explain positive selection

• Positive selection ensures we express T-cells that can bind to our MHC molecules.

  

What happens to T-cells that have TCRs specifically for self-MHC?

• they travel inti the thymic stroma towards the corticomedullary junction.

What is negative selection for T-cells?

• negative selection for binding of TCR to self-peptides and deletion

  

• to make sure the T-cells dont attack the body

What is AIRE and where is it expressed?

Autoimmune Regulator — transcription factor expressed in medullary epithelial cells of the thymus. Drives expression of tissue-specific peptides (e.g. insulin) so autoreactive T cells can be deleted before leaving the thymus.

What happens if AIRE is deficient?

Tissue-specific peptides are not presented in thymus → autoreactive T cells escape to periphery → attack tissues → autoimmunity (e.g. APECED)

What is central tolerance and what does it prevent?

Deletion of autoreactive T cells in the thymus. Prevents T cell responses against self-peptides in the absence of infection → avoids autoimmunity

How do Tregs arise and what activates them?

Arise from autoreactive CD4+ T cells during negative selection that are NOT deleted → instead activate transcription factor Foxp3 → become Tregs

How do Tregs suppress autoreactive T cells?

Must interact with the same APC as the autoreactive T cell → suppress via anti-inflammatory cytokines (e.g. IL-10, TGF-β)

What happens to T cells after passing thymic selection?

Exit thymus as mature, self-tolerant, MHC-restricted CD4 or CD8 T cells → enter blood circulation → recirculate through secondary lymphoid organs until they encounter their specific antigen

What is lymphocyte recirculation and why does it matter?

T cells continuously cycle between blood → secondary lymphoid organs (via arteries) → exit via lymphatics → back to blood. Ensures naïve T cells keep patrolling until they find their antigen.