Clarifying T cell ‘exhaustion’

Researchers in the Perelman School of Medicine have illuminated an important limitation of the immune system in prolonged battles against cancers or viruses: T cells, which are among the most powerful weapons in the immune systems of humans and other vertebrates, remain substantially programmed to stay exhausted even many weeks after exposure to a virus ended. The findings were published in Nature Immunology.

microscopic rendering of a virus cell next to a t cell.

Scientists have known that T cells can lose their ability to fight viruses and tumors when they have prolonged exposure to these enemies. They have hoped that this “T cell exhaustion” phenomenon could be reversed relatively easily, for example when the T cells are no longer exposed to the virus or tumor in question. Scientists now will need to take into account this limitation, including when devising immune-based therapies against chronic viral infections and cancers.

“Our findings suggest that once T cells become exhausted, they remain fundamentally ‘wired’ to be exhausted—thus it may be hard to get them to become effective virus- and cancer-fighters again,” says study senior author E. John Wherry, chair of the department of Systems Pharmacology and Translational Therapeutics and director of the Penn Institute of Immunology in the Perelman School of Medicine.

The recognition of the T cell exhaustion problem emerged about two decades ago from studies of long-term viral infections, including studies by Wherry and his laboratory. Scientists eventually concluded that long-term exposure not only to viruses but also cancerous tumors could exhaust T cells. Exhausted T cells start producing much lower amounts of immune response-stimulating proteins, and generally become less able to kill virus-infected cells or tumor cells.

Researchers have hoped that by blocking certain activity-inhibiting receptors on exhausted T cells, they could reinvigorate the T cells in cancer patients and in patients infected long-term with viruses such as HIV or Hepatitis C virus. However, there is evidence now that such reinvigoration, for example with cancer drugs called PD-1 inhibitors, tends to be incomplete and temporary.

Read more at Penn Medicine News.