CDC, JAMES GATHANYT cells that specifically recognize dengue virus also express a surface marker that directs them to the skin, according to a study published today (March 11) in Science Translational Medicine. The discovery of skin-homing T cells could have important implications for dengue vaccine design.
“The concept that T cells are really going to be important for controlling natural dengue infection, and now in the context of dengue vaccination, is really big for the field,” said Sujan Shresta of the La Jolla Institute for Allergy and Immunology who was not involved in the research. “It’s really a paradigm shift.”
Dengue, a mosquito-borne infection that affects approximately 100 million people per year worldwide, comes in four different forms, or serotypes. Infection with one serotype provides lifelong immunity to that variant, but at most a year of protection from the other serotypes. After this period, secondary infection with another serotype results in severe disease. Researchers ascribe this puzzling response either to antibodies generated during the first infection or to T cells that play a role in dengue pathogenesis. For many decades, research and vaccine design has focused on the antibody hypothesis. The role of T cells was not clear, although recent studies in people and mouse models have suggested that the T cells may play a protective—rather than a pathogenic—role.
Laura Rivino at the National University of Singapore and her colleagues characterized dengue-specific T cells from patients by searching for tissue-specific markers on the cells. While they initially hoped to find gut-homing markers that could explain some of the gastrointestinal symptoms of dengue, such as abdominal pain and bleeding, the researchers instead found that the T cells expressed cutaneous lymphocyte-associated antigen (CLA), which targets cells to the skin. Although dengue affects the entire body, directing T cells to the site of the infecting mosquito bite would allow the cells to make initial contact with the virus.
The scientists demonstrated that these cells recognize the virus, produce signaling molecules to trigger an immune response, and cause infected cells to burst. They also showed that the cells are present in the skin of dengue patients, but not in healthy controls, by isolating the cells from skin blister fluid. “The fact that you have these dengue-specific T cells in the skin of these patients that are infected with dengue and then they resolve it could point to an important protective role of these cells,” Rivino said.
The findings could also help to explain why a Sanofi dengue vaccine currently in clinical trials has so far shown disappointing results. The vaccine, which contains the dengue structural proteins targeted by antibodies but not the parts of the virus known to trigger a T-cell response, appears to provide protection only to patients who have already been exposed to dengue, and does not protect well against two of the four serotypes. “Even WHO [World Health Organization], in a consensus panel, has taken neutralizing antibodies as the main outcome for an effective novel dengue vaccine,” said Esper Kallas of the University of Sao Paulo who was not involved in the research. The results of this latest study, he added, raise the important question of “whether we should also focus on CD8 T cell induction using novel vaccines.”
“When you vaccinate, you want to generate not only cells that recognize the particular pathogen but also that are going to the right place,” said Rivino.
“It gives a blueprint for what kind of T cell response should be induced,” Shresta agreed.
The results could also provide insight into the week-long rash that human patients develop after running a fever, which could be due to the skin-homing T cells degrading the virus and triggering an inflammatory immune response, Kallas explained. The skin-targeted T cells could also account for the increased amounts of virus found at the skin in mouse and monkey models, Shresta added.
In future studies, Rivino and her colleagues aim to better understand the relationship between skin-targeted dengue T cells and those in circulation. Shresta said she is excited about the work because it allows her to test whether the skin-homing dengue-specific T cells play a protective role in a mouse model of the disease.
L. Rivino et al., “Virus-specific T lymphocytes home to the skin during natural dengue infection,” Science Translational Medicine, doi:10.1126/scitranslmed.aaa0526, 2015.