Cells infected with the hepatitis C virus accumulate large lipid droplets, a phenomenon called steatosis which contributes to the development of liver fibrosis in patients with chronic hepatitis C. © Inserm, P. Roingeard
Chronic infections and cancers induce functional depletion of T lymphocytes, key cells of the immune system. These are then no longer able to perform their function correctly. The revitalization of exhausted T lymphocytes is a major therapeutic issue. The work of researchers and teacher-researchers from Inserm and the University of Paris at the Saint-Louis Research Institute, in collaboration with teams from Harvard University (United States) suggests that a therapeutic intervention early is essential to preserve T cell functionality and that, after a certain period of time, T cells develop abnormalities in gene expression and can no longer fully recover. This work greatly improves our current knowledge of the mechanisms of exhaustion of the immune system and identifies new potential therapeutic targets for the treatment of cancers and chronic infections. The results are published in the revue Nature Immunology.
T lymphocytes are key cells in the adaptive immune response. Responsible for cellular immunity, their role is to destroy the cells of the body infected by a virus or tumor cells. However, with chronic infection or cancer, there is a depletion of T cells over time. In other words, chronically stimulated by viral or tumor proteins, T lymphocytes are no longer able to perform their function and kill infected or cancerous cells. They cannot differentiate into memory T lymphocytes, capable of inducing a booster immune response in the event of a new infection or cancer relapse.
This dysfunction results in genetic and molecular alterations which have been studied at length by scientists, in order to understand how this depletion of T lymphocytes takes place. In addition, the revitalization of exhausted T lymphocytes is a major therapeutic issue and a whole other area of research is interested in how to achieve this. We now know that certain immunotherapies can lead to this revitalization of T lymphocytes, but they work unevenly from one patient to another.
The new study conducted by Inserm researcher Pierre Tonnerre and his colleagues at the Saint-Louis Research Institute (Inserm / University of Paris), in collaboration with teams from Harvard University in the United States, focused on mechanisms of T cell depletion in the context of hepatitis C virus infection.
Hepatitis C is the only chronic viral infection today that can be completely cured with direct-acting antivirals (DAAs).
In this work, the researchers studied the functional and molecular characteristics of T lymphocytes from 20 patients long-standing infected with the hepatitis C virus and treated with DAAs for 12 weeks in a clinical trial. . The idea was to study how depleted T cells change when they are no longer chronically stimulated by viral proteins, after patients have recovered.
They first observed that, following 12 weeks of therapy, in cured patients, the T lymphocytes seemed to differentiate and acquire the characteristics of normal memory T lymphocytes. However, this is only a decoy: Upon closer inspection, they noticed that the key parameters that determine the effectiveness of these cells remained dysfunctional. At the molecular level, the expression of certain genes remains altered, as if the exhaustion of lymphocytes during infection had left a “scar”.
“The longer the stimulation of the T lymphocytes by the viral proteins, the deeper the scar. Our work therefore suggests that an early therapeutic intervention could make it possible to better conserve the functionality of T lymphocytes and to fight against their depletion. After a certain period of time, the genetic abnormalities set in over time, and the T lymphocytes are no longer able to recover and perform their functions correctly ”, explains Pierre Tonnerre.
The implications of this work are important, since they provide new knowledge on the mechanisms of exhaustion and functional recovery of exhausted T lymphocytes. They also pave the way for the identification of potential therapeutic targets.
“In the longer term, we can imagine testing and developing new therapies that will target regions of altered T lymphocytes genes and which could have a benefit in the treatment of chronic infections and cancers by helping these cells to regain their functions” , emphasizes Pierre Tonnerre.
However, the next step in this work is to see if treating patients with chronic hepatitis C earlier, during the acute phase of infection, allows T cells to regain better functionality.
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