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