Study finds unbalanced response worsens lung infections

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CD4+ T cells have been highlighted in the scientific literature for their important role in the immune response to lung infections. But an article published in the journal Cell report shows that an imbalance in the volume of these immune cells in different parts of the lung in response to infection can do more harm than good.

The research described in the article involved infecting mice with hypervirulent tuberculosis and influenza. The authors concluded that an “ideal amount” of CD4+ Lung T cells were needed for healing. This discovery opens up perspectives for therapeutic interventions aimed at fighting diseases that invade the lungs, while not affecting the ability of the adaptive immune system to fight infection. Even a relatively small number of CD4+ For example, lung T cells have been shown to be sufficient to prevent tuberculosis.

The researchers found that the amount of these cells in the lung tissue is mediated by a specific receptor called P2RX7, a protein that is primarily expressed on immune cells and is able to detect the presence of extracellular adenosine triphosphate (ATP). ATP’s main functions are related to energy production for cells, but it can be released into the external medium in response to stress or tissue damage, acting as a danger signal to immune cells and potentially leading to an increased response.

In such cases, P2RX7 generates an excess of CD4+ Increases expression of T cells and the chemokine receptor CXCR3 (chemokines are proteins that cause white blood cells to migrate to infected or damaged tissue). According to the article, excessive buildup of CD4+ Mice lung T cells induced by P2RX7 activation correlated with increased disease severity and decreased survival.

ATP in the extracellular medium is recognized by the immune system as a sign of damage because it should be inside the cell instead of outside. Previous research shows how important it is for the development of severe forms of tuberculosis, but the mechanisms are not understood. In particular, we didn’t know which cell types expressed it the most. This was what we set out to investigate. We wanted to find a way to improve the response of these T cells. What we didn’t expect was that removing the receptor to block recognition of ATP would lead to improvement, not deterioration.”


Igor Santiago-Carvalho, first author of the article

He holds a PhD in Immunology and is a researcher at the Institute of Biomedical Sciences (ICB-USP) of the University of São Paulo, Brazil.

Santiago-Carvalho’s work was supervised by Maria Regina D’Imperio Lima, first author of the article and a professor at ICB-USP. He has been researching cellular immunology for 20 years, mainly in malaria, Chagas disease and tuberculosis.

“The more we know about the factors that determine whether the immune response is deficient, optimal or excessive, the more we will be able to control it with drugs and treatments and even cure the disease,” Lima said.

T cells, or T lymphocytes, are key players in the immune response, which they stimulate and regulate. “For this reason, we wanted to find out which signaling pathways influence immune response optimality. We realized during the project that when tissue is badly damaged, it releases a lot of damage signals,” he explained. “We were particularly concerned with ATP, and we found that the inflammatory response is intense and harmful when too many T cells enter the tissue when they recognize ATP. In some cases, this leads to pulmonary fibrosis. This can interfere with the signaling pathway. Excessive resistance to infection. There must be an effective means of reducing the harm caused by power.”

The research was supported by FAPESP through a thematic project grant awarded to Lima and a direct doctoral scholarship awarded to Santiago-Carvalho.

TB is still a major public health problem worldwide

Tuberculosis is still considered one of the world’s major public health problems, now exacerbated by the emergence of drug-resistant bacteria. It is a contagious infectious disease that mainly affects the lungs, primarily spread through the air in droplets when the patient sneezes, coughs or talks.

The usual symptoms are a persistent cough, dry at first and with phlegm after four weeks; excessive fatigue; low fever; night sweats; loss of appetite; and weight loss.

The disease can become serious if not treated promptly and the bacteria responsible is hypervirulent. Patient sensitivity is also a factor in exacerbations, which are often associated with a deleterious inflammatory response leading to respiratory distress and even pulmonary necrosis. Treatment requires a six-month regimen of antibiotics, which cannot be interrupted or administered irregularly.

In 2022, 7.5 million new cases of tuberculosis will be diagnosed and reported worldwide, the highest number since the World Health Organization (WHO) began global surveillance in 1995. This increase was thought to be mainly due to an increase in diagnosis and treatment by health. Service.

Next step

Initially designed to focus on tuberculosis, the study also examined the role of T cell-specific P2RX7 in mice infected with influenza. The results were similar. “It has strongly influenced what I’m doing as I continue to study how damage signaling regulates the immune system,” says Santiago-Carvalho. “In the article, we concluded that CD4+ T cells can be pathogenic. We now want to understand what causes this increased pathogenicity, which we aim to define while determining the underlying mechanisms and potentially extend their analysis to other diseases. If we can understand the properties of these cells that cause a strong enough response to tissue damage, we may be able to develop alternative therapies.”

Santiago-Carvalho is currently in the Department of Immunology at the Mayo Clinic in the United States, working in the laboratory led by Henrique Borges da Silva, the article’s last author and principal contact.

Source:

Journal Reference:

Santiago-Carvalho, I., etc. (2023). T cell-specific P2RX7 favors lung parenchymal CD4+ T cell accumulation in response to severe lung infection. Cell report. doi.org/10.1016/j.celrep.2023.113448.



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