Chronic Infections and Cancers Can Lead To Functional Exhaustion of T Cells

T cells play a central role in the immune response. In order to better treat cancer and chronic infections, a recently published study investigated the mechanisms of T cell exhaustion during hepatitis C virus infection.

Chronic infections and cancer lead to functional exhaustion of T cells, the key cells of the immune system. They are then no longer able to perform their functions properly.

T Cell

T Cell

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Revitalizing exhausted T lymphocytes is a major therapeutic challenge. Work by scientists and faculty researchers at Inserm and the Institut de Recherche Saint-Louis at the University of Paris, in collaboration with teams from Harvard University, showed that early therapeutic intervention is essential to maintain T cell function and that T cells, after a delay, develop abnormalities in their gene expression and are unable to fully recover. This work significantly improves the current knowledge on the mechanisms of immune exhaustion and identifies potential new therapeutic targets for the treatment of cancer and chronic infections. The results of this study were published in Nature Immunology.

Understanding the mechanisms of T cell exhaustion

T lymphocytes are key cells of the adaptive immune response and are responsible for destroying cells in the body that have been infected by a virus or malignant cells. However, in the case of chronic infection or cancer, T cells eventually become exhausted. In other words, when T cells are constantly stimulated by viruses or tumors, they can no longer perform their function of killing infected or cancerous cells. They cannot differentiate into memory T-cells that can boost the immune response in the event of a new infection or cancer relapse.

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This dysfunction leads to genetic and molecular changes, which scientists have already studied in-depth to understand how T-cell exhaustion occurs. In addition, reviving exhausted T-cells is a major therapeutic challenge, and another area of research is how to achieve this. It is now known that certain immunotherapies can revive T lymphocytes, but they do not affect all patients in the same way.

The new study by Inserm researcher Pierre Tonnerre and his colleagues at the Institut de Recherche Saint-Louis (Inserm/University of Paris), in collaboration with teams from Harvard University in the United States, looked at the mechanisms of T cell exhaustion associated with hepatitis C virus infection.

Maintaining their function is essential

Hepatitis C is currently the only chronic viral infection that can be completely cured by direct-acting antiviral drugs (DAAs). In this study, researchers investigated the functional and molecular properties of T cells from 20 patients with long-term hepatitis C infection treated with DAAs for 12 weeks in a clinical trial. The aim was to investigate how weakened T cells would change once the patients recovered and were no longer continuously stimulated with viral proteins.

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They observed that after 12 weeks of treatment, the T cells of the cured patients differentiated and acquired the normal properties of memory T cells. However, this is was just an illusion: a closer look revealed that the key parameters determining the effectiveness of these cells remained dysfunctional. At the molecular level, the expression of certain genes remained altered, as if the exhaustion of the lymphocytes during the infection had left a “scar”.

T cells do not always fully recover when chronic infections and cancers are cured

Early therapeutic intervention can better preserve T-cell functionality and prevent T-cell exhaustion

“The longer T-cells were stimulated by viral proteins, the deeper the scarring. Our work, therefore, suggests that early therapeutic intervention may better preserve T-cell functionality and combat T-cell exhaustion. Over time, genetic defects develop and T lymphocytes are no longer able to recover and perform their functions properly,” explains Pierre Tonnerre.

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The implications of this work are important because it provides new insights into the mechanisms of exhaustion and functional recovery of exhausted T lymphocytes. It also opens the way to the identification of potential therapeutic targets.

“In the longer term, we can consider testing and developing new therapies that target altered gene regions of T lymphocytes and that could be useful in the treatment of chronic infections and cancer by helping these cells to recover their functions,” Pierre Tonnerre points out.

However, the next step in this work is to see whether treating patients with chronic hepatitis C at an earlier stage, during the acute phase of infection, allows T cells to better recover their functionality.


Differentiation of exhausted CD8+ T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory



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