T cell exhaustion

T cell exhaustion refers to a T cell dysfunction caused by chronic antigen exposure. 


It can occur in cancers and affect tumor response to therapy.


T cell exhaustion refers to the progressive loss of effective functions and have the decreased ability to produce cytokines and increased expression of inhibitory receptors. 



Upregulated inhibitory receptors can downregulate effective functions upon binding to inhibitory ligands or soluble factors in the tumor microenvironment.



Antigen exposure of acute or intermittent nature allows T cells to differentiate into memory T cells, but persistent antigen exposure prevents recovery to a normal memory differentiation.



With T cell exhaustion there is over expression of immune checkpoints and inhibitory molecules.

T cell exhaustion refers to the state of dysfunctional T cells, characterized by progressive loss of function, changes in transcriptional profiles and sustained expression of inhibitory receptors. 

T cells at first cells lose their ability to produce IL-2 and TNFα followed by the loss of high proliferative capacity and cytotoxic potential, eventually leading to their deletion. 

Exhausted T cells typically indicate higher levels of CD43, CD69 and inhibitory receptors combined with lower expression of CD62L and CD127. 

Exhaustion can develop during chronic infections, sepsis and cancer.

Exhausted T cells preserve their functional exhaustion even after repeated antigen exposure.

Antigen exposure also has effect on the course of exhaustion because longer exposure time and higher viral load increases the severity of T cell exhaustion. 

At least 2–4 weeks exposure is needed to establish exhaustion.

Another factor able to induce exhaustion are inhibitory receptors including programmed cell death protein 1 (PD1), CTLA-4, T cell membrane protein-3 (TIM3), and lymphocyte activation gene 3 protein (LAG3).

These overexpressed molecules include PD-1, cytotoxic T lymphocytes 4, CD 160, and lymphocytes-activation gene 3 (LAG-3), T cell immunoglobulin domain and mucin domain containing protein 3.

Treg cells can be a source of IL-1can play a role in T cell exhaustion.

T cell exhaustion is reverted after depletion of Treg cells and blockade of PD1.

T cell exhaustion can also occur during sepsis as a result of cytokine storm. 

The higher the number of expressed inhibitory receptors, the greater the degree of T cell exhaustion.


With T cell exhaustion the ability to produce some cytokines is usually lost: loss of IL- 2 often occurs early, and the inability to produce interferon-gamma is characteristic of severe exhaustion.


Sepsis carries high antigen load and inflammation, increasing T cell exhaustion.

T cell exhaustion can develop following persistent antigen exposure after graft transplant.

T cell response diminishes over time after kidney transplant, suggesting T cell exhaustion plays an important role in tolerance of a graft mainly by depletion of alloreactive CD8 T cells.

Studies show positive effect of chronic infection on graft acceptance and its long-term survival mediated partly by T cell exhaustion.

Recipient T cell exhaustion provides sufficient conditions for NK cell transfer.

The induction of T cell exhaustion can be beneficial for transplantation it also carries disadvantages among which can be counted increased number of infections and the risk of tumor development.

During cancer T cell exhaustion plays a role in tumor protection. 

According to research ome cancer-associated cells as well as tumor cells themselves can actively induce T cell exhaustion at the site of tumor.

T cell exhaustion can also play a role in cancer relapses n leukemia.

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