17- T cell development

• Where do T Cells Come From

  1. HSC to Hematopoetic precursor (common lymphoid progenitor)

  2. Migrates to Thymic Cortex to become T-cell Precursor

  3. Multiple stages and sub-stages to T cell development
• Stages of T cell development

  • Double Negative (DN)
  • Double Positive (DP)
  • Single Positive (SP)
• Double Negative (DN)

  1. DN1: Cells enter thymus and proliferate as soon as they do

  2. DN2: Most end up getting killed so need to start with lots to have a decent yield, TCR B chain rearrangement: D to J, Rag1/2 Expression, Not committed to being a T cell yet

  3. DN3: Fully committed to by thymocyte, V to DJ, A surrogate pre TCR alpha chain is used, C3b is expressed, Allelic exclusion: 2 tries. If second one fails apoptosis, Rag 1/2 stops

  4. DN4: End of B chain rearrangement, Proliferation: need to have lots of daughter cells for a chain rearrangement
• Double Positive Thymocytes

  • CD4 and CD8 expressed on surface, Rag 1/2 back on, Rearrangement of a chain of TCR :V to J, Can retry multiple times, Low levels of TCR is expressed on surface
• Going from DP to SP

  1. Positive selection: TCR needs to recognize self MHC, Useful ones are kept and non-functional ones eliminated, Based on weak binding to MHC and self antigen, Cells decide if going to bind to MHC I (CD8) or MHC (CD4)

  2. Negative Selection: Strong avidity binding to self antigens apoptosis, Ensures central tolerance
• AIRE

  • Transcription factor will randomly turn on genes all over the place
• 97% of t cells die in thymus because bonding can't be too weak or too strong!
• How are Self Peptides Expressed in the Thymus

  1. mTEC: Medullary thymic epithelial cells express AIRE, Allows the cells to express, process and present proteins normally not found in the thymus in context of MHCI, Still not able to present ALL self antigens so selection can occur out in periphery later as well (mostly apoptosis)

  2. Dendritic Cells: Phagocytosis of mTEC, present self peptides on MHC II
• CD4/CD8 Commitment: Kinetic Signalling Model

  Cell with both 4 and 8 has CD 8 turned off, Presented with AG and MHC I: If disrupted signalling: turn CD4 off and CD8 back on, Presented with AG and MHC II: If continuous signalling: leave CD 4 on and CD8 off
• Apoptosis: allows cells to die without causing inflammation