Like marathoners who have run 26 miles and shrubs that have run out of water due to heat waves, fatigue is an unavoidable fact of life. Dogs are exhausted after grazing sheep. Birds go to night after spending a tired day flying and singing. The same is true for T cells, the mainstay of the immune system — they are exhausted.
As more researchers turn their attention to this anomalous phenomenon, T cell I’m too tired to work. An international team of researchers foresaw the possibility of reversing fatigue.The purpose is to cheer up a warrior of cells beaten by bacteria and suckers Tumor cells It was worn out and I couldn’t fight.
T cell depletion refers to dysfunction caused by chronic antigen stimulation. Antigens are proteins from infectious pathogens or tumor cells that are recognized as exogenous and dangerous by healthy T cells. Antigens are the reason why T cells elicit all arrests when they initiate an immune response and eliminate criminals.
Taking a strong and lasting response can be ineffective and have fatal consequences. T cells react to foreign antigens via their receptors (T cell receptors) or simply TCRs. Receptors recognize and respond to antigens through powerful signaling functions. However, as is common in major persistent infections, antigen overstimulation of the TCR can impair T cell signaling and exhaust TCR’s ability to respond effectively to threats.
In a joint study involving US and Japanese scientists, researchers scrutinized T cell depletion and looked at when it would occur. In addition, they identified important proteins embedded on the surface of T cells. Transmembrane protein It acts as a marker for T cell depletion. Under widespread malaise, scientists have found that a transmembrane protein named Tim-3 alone means T cell depletion.
The presence of this transmembrane protein stands as strong evidence that persistent and overwhelming antigen exposure results in the depletion of TCR signaling, even with the deletion of vast numbers of T cells. These warriors can be exhausted under the constant pressure of fighting criminals who cannot easily be knocked out.
“The transmembrane receptor Tim-3 is thought to inhibit T cell activation because it is abundantly increased in depleted T cells and is considered a therapeutic target for reactivating the antitumor response.” Drs writes.Lawrence P. Kane and Shunsuke Kataoka, author of the journal’s T cell depletion study Scientific signaling..
Lane is a researcher at the University of Pittsburgh. Kataoka studied abroad at university as a graduate student, but he is also a staff member of Asahi Kasei Pharmaceutical Co., Ltd. in Shizuoka City. They work with an interdisciplinary team at the University of Pittsburgh, where Tim-3 not only acts as a marker for T cell depletion, but surprisingly stimulates some depleted T cells to resume signaling. I found that.
Using various imaging techniques, the international team has determined that Tim-3 is an important point of contact with antigen-presenting cells, such as the T cell immunological synapse, the site of contact with dendritic cells (which literally presents T cells). Demonstrated to be mobilized to the invader’s antigen that broke the body).
Due to the impact of Tim-3, enhanced signaling may be resumed downstream in some TCRs. Despite the resumption, it is clearly not enough to reactivate an army of depleted T cells. However, now that we know how some T cells are revived, it is theoretically possible to intervene in drug booster immunization.
Investigating T cell depletion is not a new research effort. Some studies date back nearly 30 years. For example, a 1993 animal study examined viral persistence in acutely infected immunocompetent mice. Researchers found that viral persistence led to the depletion of antiviral cytotoxic effector T cells.
Immunologists first described the depletion of T cells that occur in response to chronic viral infections, but found that a strong T cell response to cancer can also cause TCR dysregulation.
Fatigue is well documented in various subpopulations of T cells. A significant amount of research has been directed to CD8 + T cells, especially a subpopulation known as cytotoxic T cells. These are important for the destruction of cancerous or virus-infected cells. CD4 + T cells have also been shown to develop functional unresponsiveness after chronic infection.
The very act of fighting long-term infiltrators can irreparably weaken the strength of T cells. This is especially true if T cells are involved in a fight to stop an infectious disease of significant public health concern. Hepatitis B and C, or HIV, human immunodeficiency virus.
In addition to research by the teams at Lane, Kataoka, and the University of Pittsburgh, two studies have been published in the journal. Nature immunology Recently, we have delved into the possible causes of T depletion and suggested possible ways to remedy it. Lane and Kataoka suggested that T cell reactivation could restart the antitumor response, but a team at Massachusetts General Hospital in Boston could rejuvenate T cells damaged by persistent viral disease. I investigated the sex.
Dr. Georg M. Lauer, Massachusetts General, has begun a study investigating T cell fatigue as a result of hepatitis C infection.
After the patients in his study were treated and cured, Lauer et al. Discovered that T cells fighting exhausted disease were transformed in a manner similar to memory T cells, and antiviral therapy turned into T cell transformation. Suggested that it could play a role. Still, the study found that the cells weren’t as functional as real memory T cells.
“While more superficial studies may have been interpreted as actual recovery, in reality the key parameters that determine T cell efficacy did not change,” Lauer said in a statement. .. He added that changing the timing of the drug could have a strong impact on T cell savings.
“We are currently investigating whether treating HCV with direct-acting antiviral therapy during the acute phase of infection will result in complete memory differentiation of T cells, not years later. If correct, this may indicate a short window of early opportunity. Chronic infections to protect T cell function. “
Lane and Kataoka note that Tim-3 is abundant as a biomarker for depleted T cells and consider it a potential therapeutic target. Scientists say that T cells can theoretically resume antitumor activity by pharmacologically targeting the ability of Tim-3 to restart signaling.
Shunsuke Kataoka et al., Tim-3’s co-stimulatory activity requires signal transduction of Akt and MAPK and its recruitment to the immunological synapse. Scientific signaling (2021). DOI: 10.1126 / scisignal.aba0717
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Cancer and viruses are difficult to fight
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