positive and negative T cell selection in the thymus.

positive and negative T cell selection in the thymus

 A lymphoid organ is situated in the neck of vertebrates which produces T-lymphocytes for 
the immune system. The human thymus becomes much smaller at the approach of puberty.  

Cortex – immature thymocytes, epithelial cells and scattered macrophages.
Medulla- mature thymocytes, epithelial cells, macrophages and dendritic cells.
T Cell development  in the thymus: 
Step 1: T- cell progenitors develop in the bone marrow and migrate to the thymus-  T cell precursors rearranges its t cells receptor genes in the thymus. 

Step 2: positive and negative selection in the thymus- Immature T cells that recognise self MHC receive signals for survival. Those that interact strongly with self antigen are removed from the repertoire. 

Step 3: Mature T cells migrate to the peripheral lymphoid organs- Mature T cells encounter foreign antigens in the peripheral lymphoid organs are activated. 

Step 4: Activated T cells migrate  to sites of infection- Activated T cells proliferate and eliminate infection. 

T cells move through a number of different developmental stages classified by expression of CD4 and CD8 on their cell surface: They are:
• DN (CD4-8-)
• DP (CD4+8+)
• CD4SP or CD8SP




T cell precursors proliferate extensively in the thymus, but most die there. 95% of thymocytes die by apoptosis before reaching the medulla. Some die due to NEGLECT. 
NEGLECT – no TCR-MHC interaction = NO SURVIVAL SIGNAL
• Positive selection of thymocytes: development of the self MHC-restricted T cell repertoire.  The MHC type of the thymic stroma selects a repertoire of mature T cells that can recognize foreign antigens presented by the same MHC type- self restriction. 
• Only thymocytes whose TCR interact with self-peptide: self-MHC complexes weakly can survive and mature.
• Those that do not recognize the MHC molecules are killed by apoptosis (death by neglect) 
Positive selection is mediated by MHC:peptide on thymic epithelial cells 
Peptides role in positive selection: 
• Peptides presented in the thymus are self –peptides derived from widely expressed 
• Self-peptides presented cause stabilisation of MHC on epithelial cells 
• Self-peptides presented on epithelial cells influence the specificity of the T cells that are selected
• Some self peptides are better than other at positive selection
• Different peptides result in different T cell repertoires
Positive selection coordinates the expression of CD4 or CD8 with the specificity of the T-cell receptor and the potential effector functions of the T cell. This is known as lineage commitment

The Double positive (DP) thymocytes
• DPs initially express low levels of abTCR 
• 10-30% of TCRs recognise cortical epithelial cells expressing ‘self peptide’ presented by ‘self MHC’ – POSITIVE SELECTION
• Positive selection acts on a repertoire of T-cell receptors with inherent specificity for self MHC molecules.
Negative selection removes thymocytes that are capable of strongly binding with "self" MHC peptides. Thymocytes that survive positive selection migrate towards the boundary of the cortex and medulla in the thymus.The remaining cells exit the thymus as immature naïve T cells.

Negative selection of thymocytes: Central Tolerance
• T cells that react strongly (high avidity/strong interaction) with ubiquitous self antigens are deleted in the thymus or become regulatory T cells
• Can occur at the DP or SP stages 
• Can be induced by bone marrow derived antigen-presenting cells in the cortex and medulla such as DCs and macrophages
• thymic medullary epithelial cells can also induce negative selection 

Negative selection is driven by bone marrow derived antigen-presenting cells (DCs and macs) and medullary epithelial cells.

**!!REMEMBER TO STAY POSITIVE LIKE A PROTON!!**