Scientists at the German Cancer Research Center (DKFZ) say they have now found evidence in mice that skeletal muscles help to keep the immune system functional in chronic diseases. They published their study “Skeletal muscle antagonizes antiviral CD8+ T cell exhaustion” in Science Advances.

“CD8+ T cells become functionally impaired or ‘exhausted’ in chronic infections, accompanied by unwanted body weight reduction and muscle mass loss. Whether muscle regulates T cell exhaustion remains incompletely understood. We report that mouse skeletal muscle increased interleukin (IL)–15 production during LCMV clone 13 chronic infection. Muscle-specific ablation of Il15 enhanced the CD8+ T cell exhaustion phenotype. Muscle-derived IL-15 was required to maintain a population of CD8+CD103+ muscle-infiltrating lymphocytes (MILs). MILs resided in a less inflamed microenvironment, expressed more T cell factor 1 (Tcf1), and had higher proliferative potential than splenic T cells,” write the investigators.

“MILs differentiated into functional effector T cells after reentering lymphoid tissues. Increasing muscle mass via muscle-specific inhibition of TGFb signaling enhanced IL-15 production and antiviral CD8+ T cell responses. We conclude that skeletal muscle antagonizes T cell exhaustion by protecting T cell proliferative potential from inflammation and replenishing the effector T cell progeny pool in lymphoid organs.”

In many cases, such as cachexia, severe weight loss and a decrease in muscle mass are the result of cancer or dangerous infections. Patients also often suffer from a weakened immune system. One of the reasons for this is a loss of function of a group of T-cells, whose task it is to recognize and kill virus-infected cells or cancer cells.

The processes leading to loss of T-cell activity are still largely unexplained. However, first indications suggest that there is a connection with cachexia.

“It is known that T-cells are involved in the loss of skeletal muscle mass. But whether and how, in turn, skeletal muscles influence the function of the T-cells is still unclear,” explains Guoliang Cui, PhD,  from the DKFZ.

To find out, the scientists infected mice with lymphocytic choriomeningitis virus (LCMV). This method is a widely used model system to study the course of acute or chronic infections in mice. The researchers then analyzed the gene expression in the skeletal muscles of the animals and found that in chronic infections, the muscle cells release an increased amount of the messenger substance interleukin-15. This cytokine causes T-cell precursors to settle in the skeletal muscles. As a result, they are spatially delimited and protected from contact with the chronic inflammation.

“If the T-cells, which actively fight the infection, lose their full functionality through continuous stimulation, the precursor cells can migrate from the muscles and develop into functional T-cells,” said Jingxia Wu, PhD, lead author of the study. “This enables the immune system to fight the virus continuously over a long period.”

So could regular training strengthen the immune system?

“In our study, mice with more muscle mass were better able to cope with chronic viral infection than those whose muscles were weaker. But whether the results can be transferred to humans, future experiments will have to show,” explains Cui.

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