Machanism of Central T-cell Tolerance

  The lymphocytes circulating in our body express unique antigen specific receptors. When these lymphocytes encounter their specific antigen, they get stimulated and undergo proliferation to produce a clone of that specific lymphocyte. And finally they differentiate into effector cells and memory cells.

Our immune system produces nearly infinite number of lymphocytes and each of these express unique antigen receptors on their cell membrane.

Our immune system also generates lymphocytes capable of recognising self antigens. Such lymphocytes are known as autoreactive or self reactive lymphocytes. It is crucial for our immune system to make sure that only those lymphocytes mature that have the potential to recognise non-self antigens.
• This is because mature autoreactive lymphocytes will start damaging the hosts own tissues.

  T-lymphocytes originated in the bone marrow and later they migrated to the thymus for their further development. In the thymus these T lymphocytes rearrange their T-cell receptor genes.
• One of the main function of thymus is to produce T-cell receptors.
• Developing T-cells in the thymus are known as thymocytes. Each of these thymocytes have randomly generated antigenic specificity.

• T-cells recognise only peptide antigens. They don't recognize them in isolation.
• T-cells recognise peptide antigens as peptide MHC complex.
• These MHC's are our body's own molecules and therefore it's called self MHC molecules.
• T-cells recognise and bind both the MHC molecule and the peptide antigen displayed on the target cell.

Mechanisms and Processes of T-Cell Central

  When precursor T-cells from bone marrow first enter to the thymus, They lack most of the surface molecules that are characteristic of mature T-cells. Their receptor genes are also not rearranged.

  Once inside the thymus these precursor T-cells start developing and they expressed T-cell receptors of random antigenic specificity.

  During their maturation in the thymus immature T-cells undergo an elaborate screening process.
This process involves three main selection events namely
- Non selection
- Positive selection and
- Negative selection.

  All nucleated cells Express MHC class-1 molecules. Under normal conditions these MHC 1 molecules display self antigens. So thymic epithelial cells will also express MHC 1 molecules.

Bone marrow derived dendritic cells and macrophages are found these antigen presenting cells present peptide antigens in complex with MHC 2 molecules.
These peptide antigens are derived from all the proteins made by these cells. Besides this they also display peptide antigens derived from soluble proteins taken up from extracellular fluid.

• In the thymus the immature T cells will mostly interact with self antigens in complex with self MHC molecules.

According to scientists the fate of the developing T-cells in the thymus is determined by the strength with which immature T-cells interact with self peptides (self MHC complexes).

Non selection

If immature T-cells fail to recognize and bind the self antigen self MHC molecules they undergo programmed cell death or apoptosis.
- Most of these cells have non-functional T-cell receptors
- They may also lack receptors recognising MHC molecules.

   Lack of interaction between these T cells and self peptides self MHC molecule results in death of T cells. This selection event is known as non selection

Positive selection

If immature T-cells are successful in recognising these peptide MHC molecules a survival signal is conveyed to the nucleus of the immature T-cell.

Positive selection: Strength of binding is moderate

  These T lymphocytes divide and grow further. This process is known as positive selection.

Positive selection selects those immature T-cells that bind moderately to that self peptide, self MHC molecules.
- This interaction is not too strong nor too weak.
- One of the main role of positive selection is to make sure that thymocytes are capable of recognising self MHC molecules.
  T cells should learn to recognise peptide antigens in complex with MHC molecules.

Negative selection

Those immature T-cells that bind very strongly to self peptide (self MHC molecules) undergo cell death or apoptosis. Such T-cells are potential autoreactive cells.

Negative selection: Strength of binding is very strong

 This process of removal of selected T-cells is known as negative selection. Dead cells are phagocytosed by macrophages in the thymus.

T cell Tolerance Inside Thymus

• In the central T-cell tolerance immature T-cells selected by positive selection survived. 

• These are the cells with potential of recognising non-self antigens in complex with MHC molecules. These immature T-cells leave the thymus and migrate to the secondary lymphoid organs.

• Process of Negative selection removes all the potential autoreactive T-cells that recognise self antigens,

• All self antigens are not expressed in the thymus. Some self antigens may appear in other tissues or at different stages in the development of cells.

• Autoreactive T-cells recognising these self antigens escape central T-cell tolerance. They migrate successfully to peripheral lymphoid tissues where the mechanisms of peripheral tolerance prevent their maturation and eliminate them.