Wednesday, November 6, 2013

T Cell Exhaustion: A Normal Response to Viral Infections?

                T cell exhaustion is an interesting phenomenon that scientists have found to occur in chronic viral infections. This is a state in which T cell activity rapidly declines and enters a refractory period due to the presence of a virus. Initially, when a virus infects the body, specific CD8+ memory T cells (1) will produce cytokines (2) in the attempt to begin fighting off the infection. T cell exhaustion then occurs when T cells cannot function properly and cytokine production is occurring at a slower or non-existent rate (Wherry 2011). Thus, T cell exhaustion is often association with chronic viral infections such as cancer because chronic infections fatigue the immune system. Hindered T cell function affects the body’s ability to fight back against a disease, and it prevents the immune system from properly reacting to tumors and long lasting infections.
Yi, John S. et. al. T-Cell Exhaustion: Characteristics, Causes, and Conversion. April 2010. 
             Immunology. 129(4): 474-481.
Until recently, T cell exhaustion was considered to be a by-product of chronic infection, for scientists believed that it was an abnormal physiological and immunological response to the virus. However, in September an article was published by Martin Hosking and his other colleagues challenging this assumption and providing evidence for the claim that T cell exhaustion is a normal response to any type of infection: acute or chronic – or even latent. Infecting mice with one of two different types of acute viral infections, the scientists measured CD8+ T cell activity over time, looking at IFN- γ (3) cytokine production in relation to hours elapsed since primary and secondary infection. Their results indicated that acute viral infections induce T cell exhaustion as well; therefore they claimed that T cell exhaustion is a normal response to infection, and it should not only be associated with chronic viral diseases.
More specifically, the results from Hosking and his colleagues’ experiment revealed that
IFN- γ expression effectively suppressed the majority of viral activity before the virus even had a chance to completely replicate for the first time. This is because they assumed the virus to be the most vulnerable directly after the onset of infection. However, they found that IFN- γ production stopped within hours of its onset, despite the continuing presence of the antigen. This could be a consequence of the decreased amount of antigen that stimulates an immune response. These factors combined could then contribute to a loss of multifunctional T cell response and effectively could lead to exhaustion.

Hosking and his fellow researchers also found other indicators inducing T cell exhaustion; for example, there was an upregulation of inhibitory receptors on CD8+ T cells, preventing cytokine production as well. Inferring from their data, the scientists concluded that T cell exhaustion is a normal physiological response to the introduction of a viral infection. They then proposed that the decreasing acute infection causes responding CD8+ T cells to gradually and asynchronously leave their exhaustion phase in order to restore normality within the immune system. Then they hypothesized that chronic viral infections prolong the refractory phase of T cells and induce genetic and epigenetic changes that create extended T cell dysfunction.
The findings in this paper offer new insight into the occurrence of T cell exhaustion. Realizing that acute and chronic viruses both induce a T cell refractory period is important both for modern medical and scientific research. Understanding the mechanisms that trigger T cell exhaustion and treating it as a normal physiological response to a viral infection could help scientists further their research into cures for chronic viral infections. It also helps eliminate false hypotheses regarding T cell exhaustion, as many scientists will now know that this phase is not limited to chronic viral infections. Therefore, research done in this field of study will have more evidence behind it with greater certainty, further ensuring that scientists will be on the right track for new discoveries.

Primary Source:

Hosking, Martin et. al. CD8+ Memory T Cells Appear Exhausted within Hours of Acute Virus Infection.
15 October 2013. Journal of Immunology. 191(8): 4211-22.

Secondary Source:

Wherry, E. John. T Cell Exhaustion. June 2011. Nature Immunology. 12: 492-499.


Yi, John S. et. al. T-Cell Exhaustion: Characteristics, Causes, and Conversion. April 2010. 
             Immunology. 129(4): 474-481.

Further Information/Definitions:

CD8+ memory T cells:


IFN- γ:

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