T lymphocytes, or T cells, are an important part of our immune system. They recognize foreign proteins, called antigens, as peptide fragments – for example, those derived from viruses or cancer cells. In principle, they may, but usually do not, attack our (‘own’) proteins. “That’s why it’s important for the organism to tightly control T cell activity,” says Dr. Reinhard Obst, head of a research group at the Institute for Immunology at the LMU Biomedical Center that study of T cell activation. The project contributed to the 1054 Collaborative Research Center which studies the plasticity of cellular sweat determinants in the immune system.
When viruses access our tissues, T cells are activated to eliminate the pathogens. However, if T cells are exposed to their target antigens for too long, they can lose their function and become tired. ‘They no longer destroy pro-inflammatory messenger molecules, so they cannot contribute much to an immune response. Conversely, it makes sense to control these cells, in order to avoid collateral damage to the organism. T cell disruption, on the other hand, makes it difficult to fight off harmful diseases, such as those caused by HIV, hepatitis viruses and cancer cells. Understanding immune responses to such persistent threats is therefore one of the major challenges of modern medicine. “This is where T cell disruption plays an important role.” the LMU researcher says.
A new model for studying T cell disruption.
Several years ago, Obst developed an animal model that has now gained significant views. It focused on T helper cells, which mimic the CD4 signaling molecule and make up the largest subset of T cells. Each of these cells recognizes a protein fragment marked as an antigen.
To control the timing and magnitude of the specific antigen expressed in this model system, LMU scientists used a trick. Their transgenic mice were exposed to different doses of the antibiotic doxycycline, which controls the synthesis of the antigen, through their drinking water. Thus different amounts of antigen are administered to the T cells in these animals, which avoids the need for experimental infection. “In this way, we can regulate the level of antigen secreted,” Obst explains. “Our goal was to find out how the helper T cells co. -responsive responds.
The results showed that the effects were dose-dependent: In the presence of high doses of antigen, the T cells underwent apoptosis, resulting in their death by programmed cell death. At a moderate dose, however, the T cells survived but rapidly lost their viability. “We showed this state of fatigue by regulating the amount of antigen that occurred in the cells,” explains the LMU researcher. At low doses, it took several weeks for the cells to show signs of exhaustion. Upon further testing, the antigens were subsequently removed, but the cells were able to partially recover from their tired state. Such dynamic changes proved to the researchers that T-helper cells are capable of a remarkable degree of plasticity.
Supports the fight of T cells against breast diseases and cancer
Obst and his colleagues believe their decisions could have therapeutic implications. The data reveal that several transcription factors (proteins that control gene expression) and signaling pathways regulate the different states of exhaustion.
Two years ago, several groups showed that one of these transcription factors, called Tox, contributes significantly to the degeneration of T cells, another subset of T cells. When the Tox gene was eradicated, the T-killer cells were less easily excreted in an infectious disease and were able to fight more effectively a persistent virus. However, they also attacked the organs of the host animals and died earlier. The new findings show that there are several ways to dynamically convert T helper cells to different antigen loads.
Obst now hopes to identify molecules that inhibit transcription factors or signaling pathways that contribute to T cell disruption. This could provide a strategy that may support combat. T cells against chronic diseases and cancer and strengthen our natural defenses against such diseases.
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