Immune Exhaustion

Immune Exhaustion is a term referring to specific changes to immune cells known as CD8 T-killer cells that reduce their function at clearing cancer cells or virally infected cells from the body. Exhausted CD8+ T (Tex) cells in chronic infections and cancer exhibit high numbers of inhibitory receptors and have transcriptional changes compared with normal effector (Teff) or memory (Tmem) CD8+ T cells.

Following initial activation by foreign peptides bound to MHC cell receptor molecules, immature T cells replicate and reprogram to become effector T cells (TEFF), which produce inflammatory chemicals called cytokines that kill either cancer and/or virally infected cells. If an infection or tumor is cleared, the TEFF population dies, except for a small number of long-lived, smemory T cells (TMEM) capable of remounting a rapid response to the cancer or the particular virus.

However, if the TEFF cells had been incompetent at totally removing the cancer or infected cells over a short period, due to immune senescence, scarring or acclimatisation, they are said to become ‘exhausted’ and are then referred to as TEX cells. At the best they can keep these cells in check until a time comes when the virus or tumour mass of cancer cells overwhelms the TEX cells and threaten the survival of the body.

This process can occur with superantigen viruses, such as the Epstein Barr virus, that directly cause the formation of cancer cells and have the ability to erode the competency of TEFF cells

An protein called TOX, which can vary in amount in different immune cell types, is the epigenetic driver that changes TEFF cells into TEX cells. The longer TOX is expressed in a T cell the more permanent the TEX identity becomes. TOX must be eliminated and the epigenetic changes reversed to stop death.

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