Thursday, 10 June 2021

Cytotoxic T-cells : Activation & killing

 CD 8+ T-cells become Cytotoxic T-cells. Cytotoxic T-cells kill the infected cells. By doing so they eliminate the reservoir of infection. These cells are also known as killer T-cells or cytotoxic T lymphocytes (CTLs). They are named so because they directly kill the cells that display foreign antigens on their surface.

The main function cytotoxic T-cells is to kill cells, that have been infected by viruses and bacteria.
Cytotoxic T-cells(Tc) are also involved in killing of tumor cells and transplanted foreign cells.

Activation of Cytotoxic T-cells

When there is an intracellular infection,
• Dendritic cells from the site of infection migrate to nearby lymph node and present the viral antigens in the form of MHC 1 antigen complex. 

• Naive CD8 positive T-cells recognise the bound antigen. 

• At the same time nearby activated T helper type 1 cells are secreting interleukin 2.    

• Recognition of the antigen by CD8 positive T cell and the signals from T helper cells result in the activation of CD8 positive T cell. 

• This T-cell now proliferates and differentiates into effector cytotoxic T-cells & memory T- cells.

• These effectors cytotoxic T-cells secrete more interleukin-2 and become self-stimulating. Now these cytotoxic T-cells leave the lymph node and migrate to the site of infection to attack virally infected cells.

Under normal conditions -
All nucleated cells express MHC 1 molecules on their surface, which under normal conditions display the hosts proteins or self antigens. 

When there is an infection -
These cells display foreign antigens, therefore in this case viral antigens are displayed on the infected cell surface as MHC 1 antigen complex. The effector cytotoxic T-cells recognise and bind these MHC 1 antigen complex on the infected cells.
  The cells which are killed by cytotoxic T cells are known as target cells.

Activation of Cytotoxic T-cells

Killing function of Cytotoxic T- cells

To perform its killing function cytotoxic T-cells need to make a direct contact with the target cells. 

This direct contact is mediated by T-cell receptor and Co-receptor CD8.
- T-cell receptor binds the antigen displayed by MHC 1 molecule and
- CD8 binds the MHC 1 molecule.
  Once a contact has been established with the target cell, cytotoxic T-cells now undergo degranulation.
In other words the granules of the cytotoxic T-cells migrate to the site of contact and granule content is released.

   Cytotoxic T-cells contains specific cytotoxic granules which contain preformed cytotoxic effector proteins such as
   - Perforin
   - Granzymes
   - Granulysin
These proteins are synthesized and loaded into the granules as soon as the naive CD8 positive T- cell encounters its specific antigen.

Perforin forms pores in the membrane of the target cell.
  This damages the target cell and it also forms a passage for other granule contents into the target cell.

Granzymes enter the target cell through these pores and cause apoptosis or programmed cell death.
Thus the target cell is degraded from within. Granzymes trigger apoptosis in the target cell by activating enzymes such as nucleases and by damaging the mitochondria.

Granulysin also has antimicrobial activity and it contributes to apoptosis of the target cell.

These degraded cells are rapidly ingested and digested by phagocytes. The cytotoxic T-cells moves to another infected cell to perform the killing function.
Besides their main function as killer cells cytotoxic T-cells also secrete cytokines. The major cytokines secreted by killer T-cells are
- Interferon gamma (IFN-γ)
- Tumor necrosis factor alpha (TNF-α)
The main role of these cytokines is to activate macrophages and recruit them to the site of infection.

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