LMU researchers are studying T cell depletion

T lymphocytes, or T cells, Is an important component of our immune system.They can recognize so-called foreign proteins antigen, As a peptide fragment-for example, from a virus or cancer cell. As a rule, they can attack our own (“self”) proteins, but usually they do not. “That’s why it’s important for organisms to tightly control T cell activity,” said Reinhard Obst, head of the research group at the Immunology Institute at LMU’s Biomedical Center, which studies T cell activation. The doctor says. This project contributed to the Collaborative Research Center 1054, which investigates the plasticity of cell fate determination in the immune system.

When the virus accesses our tissues, T cells are activated and pathogens are eliminated. However, prolonged exposure of T cells to the target antigen can result in loss of function and “depletion”. They no longer secrete pro-inflammatory messenger molecules and therefore cannot contribute much to the immune response. On the one hand, it makes sense to put these cells under control to avoid incidental damage to the organism. On the other hand, T cell depletion makes it difficult to fight chronic diseases such as HIV, hepatitis virus and cancer cells. Therefore, understanding the immune response to chronically persistent threats such as these is one of the major challenges of modern medicine. “This is where T cell depletion plays a central role,” says LMU researchers.

A new model for studying T cell depletion

A few years ago, Obst developed animal models and now produces important insights. He focused on T helper cells, which express the CD4 marker molecule and make up the largest subset of T cells. Each of these cells recognizes the defined protein fragment as an antigen.

LMU scientists used tricks to control the timing and amount of specific antigens expressed in this model system. Their transgenic mice were exposed to different doses of the antibiotic doxycycline, which regulates antigen synthesis, via drinking water. Therefore, the T cells of these animals are presented with varying amounts of antigen, avoiding the need for infection. “In this way, we can regulate the amount of antigen produced,” Obst explains. “Our goal was to find out how the corresponding T-helper cells respond.

The results showed that the effect was dose-dependent: in the presence of high doses of antigen, T cells apoptotic and died by programmed cell death. However, at moderate doses, T cells survived but quickly lost function. “We showed this depletion by regulating the amount of antigen that cells encounter,” explains LMU researchers. At low doses, it took several weeks for the cells to show signs of exhaustion. When the antigens were removed in subsequent experiments, the cells were able to partially recover from their depleted state. With this dynamic coordination, researchers are convinced that T-helper cells can exert amazing plasticity.

Supporting the fight of T cells against chronic infections and cancer

Obst and his colleagues believe that their findings may have therapeutic implications. The data show that many transcription factors (proteins that control gene expression) and signaling pathways regulate various debilitating states.

Two years ago, several groups showed that one of these transcription factors, named Tox, contributes significantly to the depletion of another T cell subset, T killer cells. When the Tox gene is deleted, T-killer cells are less likely to be depleted by chronic infections and can fight chronically persistent viruses more effectively. However, they also attacked the organs of the host animal and died earlier. New discoveries suggest that several mechanisms are in place to dynamically regulate T helper cells to different antigen loads.

Obst now wants to identify molecules that block transcription factors or signaling pathways that contribute to T cell depletion. This may support the fighting of T cells against chronic infections and cancers and provide possible strategies to enhance our natural defenses against such diseases.