Mechanism that aggravates tuberculosis and reduces survival rates

CD4+ T cells have been highlighted in the scientific literature for the important role they play in the immune response to lung infections. However, an article published in the journal Cell Reports shows that an imbalance in the volumes of these defense cells in different parts of the lung in response to infection can do more harm than good.

The study described in the article involved infecting mice with hypervirulent tuberculosis and influenza. The authors concluded that an “ideal amount” of CD4+ T cells in the lungs was required for a cure. This finding opens up perspectives for therapeutic interventions aimed at combating diseases that attack the lungs, while not affecting the ability of the adaptive immune system to fight off infection. Even relatively small numbers of CD4+ T cells in the lungs proved sufficient to afford protection against tuberculosis, for example.

The researchers found that amounts of these cells in lung tissue are mediated by a specific receptor called P2RX7, a protein primarily expressed in immune cells and capable of detecting the presence of extracellular adenosine triphosphate (ATP). The main functions of ATP relate to energy production for cells, but in response to stress or tissue damage it may be released into the external medium, acting as a danger signal for defense cells and potentially leading to an exacerbated response.

In such cases, P2RX7 induces an excessive buildup of CD4+ T cells and boosts expression of the chemokine receptor CXCR3 (chemokines are proteins that direct the migration of white blood cells to infected or damaged tissue). According to the article, the excessive buildup of CD4+ T cells in the mice’s lungs induced by activation of P2RX7 correlated with an increase in the severity of the disease and a reduced survival rate.

“ATP in the extracellular medium is recognized by the immune system as a sign of damage because it should be inside the cell rather than outside. Previous research showed how important it is to the development of severe forms of tuberculosis, but the mechanisms weren’t understood. In particular, we didn’t know which type of cell expressed it most. This was what we set out to investigate. We also 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 an improvement and not a deterioration,” the first author of the article.

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 large amount of damage signals,” the author explained. “We were particularly concerned with ATP, and we found that the inflammatory response is intense and harmful when an excessive amount of T cells enter the tissue as they detect ATP. In some cases, it results in pulmonary fibrosis. Intervening in this signaling pathway could be an effective way to reduce the damage done by an excessive immune response to infection.”

Initially designed to focus on tuberculosis, the study also tested the role of T cell-specific P2RX7 in mice infected with influenza. The results were similar. “This strongly influenced what I’m doing as I continue to study how damage signals control immune responses,” the author said. “In the article, we concluded that CD4+ T cells can be pathogenic. We now want to understand what leads to an increase in this pathogenicity, which we aim to define while determining the underlying mechanisms and potentially extending their analysis to other diseases. If we understand the characteristics of these cells that induce a strong enough response to damage tissue, we may be able to develop alternative therapies.”