Impaired Immune Memory Leads to Chronic Viral Infections

An NIAID research team has found for the first time that people with Job’s Syndrome, a rare immune deficiency disease that makes people more susceptible to bacterial and fungal infections, have a lower number of immune memory cells, making them also susceptible to viral reactivation. The team’s findings, which appear in the November 23 issue of Immunity, offer clues about how immune cells in healthy people control chronic viral infections and provide a potential new treatment strategy for people with Job’s Syndrome.

Background
Electron micrograph of varicella zoster viral particles taken from a patient with chickenpox. Credit: CDC/ Dr. Erskine Palmer
The human immune system forms specialized memory cells each time it encounters a new virus. People rely on these circulating immune memory cells to protect them during subsequent exposures to the virus. This development of immune memory is a key reason why vaccines are so effective. A viral vaccine contains parts of a virus that elicit an immune response. This response generates infection-fighting memory cells, usually without causing illness or with only causing mild symptoms. If a person encounters the virus again, vaccine-induced memory cells provide the necessary protection.
Varicella zoster virus (VZV) is the virus that causes chickenpox. When the immune system encounters VZV, it makes memory cells as described above, but the virus remains in the body for the remainder of a person’s life. Many people will not become sick again, but in some people VZV can reactivate and cause shingles.

Results of Study
The NIAID research team, led by Joshua Milner, M.D., examined patients with Job’s Syndrome to better understand how immune memory develops. Job’s Syndrome, also called autosomal-dominant hyper-immunoglobulin E syndrome, is a condition caused by a mutation in a gene for the protein STAT3. One of the many functions of STAT3 is to aid in the development and specialization of specific types of immune memory T cells, a process which has been studied extensively in mice. The overall role of STAT3 in memory T cells is less understood.

The NIAID team observed that, when compared to healthy people, patients with Job’s Syndrome lack a major population of circulating memory T cells, called central memory T cells, which are thought to be a source for long-term T-cell memory. The team found that T cells rely on STAT3 to turn on genes that tell them to become central memory T cells; with the mutated STAT3 seen in people with Job’s Syndrome, the T cells do not receive sufficient signals telling them to specialize.

While previously it was thought that viral complications were not observed in patients with Job’s Syndrome, the team actually found that these patients have a significantly higher chance of developing shingles at a young age (less than 50 years old) and of experiencing repeated episodes of shingles, compared to healthy people. The team found that low numbers of central memory T cells are closely associated with these patients’ increased susceptibility to VZV reactivation.
This observation is unique because people with Job’s Syndrome do not typically experience severe chickenpox or have difficulty clearing the initial infection. This makes Job’s Syndrome one of the only diseases that predisposes patients to developing shingles, but does not affect their response to chickenpox.

Significance
Many studies of Job’s Syndrome have focused on the role of STAT3 in antibacterial and antifungal activities; this study reveals a role for STAT3 in antiviral processes.

In the general population, cases of chickenpox have decreased significantly after the introduction of the chickenpox vaccine, but even vaccinated people can experience episodes of shingles. Based on the work by the NIAID team, it is possible that people who have shingles may have decreased numbers of central memory T cells or other problems with STAT3 activity. Measuring circulating central memory T cells, or STAT3 function, could be a way to identify someone who is at greater risk for developing shingles and could benefit from the shingles vaccine, which today is recommended for use only in adults aged 50 and older. New therapeutics that boost the activity of STAT3 also could help protect people from VZV reactivation.

Next Steps
Further study is needed to determine if young, otherwise healthy people who experience episodes of shingles have impaired memory T cells. Research also is needed to better understand what level of immune memory is needed to protect people who have received the chickenpox vaccine from developing shingles.

This study also opens up the possibility of exploring chickenpox vaccination as an additional treatment for people with Job’s Syndrome. Because people with this syndrome experience numerous adverse health conditions, preventing chickenpox or shingles would greatly improve their overall quality of life. More research is needed, however, to determine the safety of giving immune-compromised patients the chickenpox vaccine.