Researchers at Emory Vaccine Center have demonstrated that exhaustion is driven by how the immune system detects infecting viruses.
To recognize the presence of a viral infection, T cells must be presented with bits of viral protein in a molecular frame supplied by other cells in the body -- called MHC (major histocompatibility complex) class I molecules.
In mice infected by lymphocytic choriomeningitis virus (LCMV), T cells became more or less exhausted depending on how much properly framed viral protein was available.
Insights from the research could guide efforts to revive the immune system in people with chronic viral infections. The results are published online this week in the Proceedings of the National Academy of Sciences.
Working with Vaccine Center director Rafi Ahmed, PhD, postdoctoral fellow Scott Mueller, PhD, examined the effects of limiting what kind of cells could display the viral antigens.
Ahmed is professor of microbiology and immunology at Emory University School of Medicine and a Georgia Research Alliance Eminent Scholar.
By performing bone marrow transplants on genetically engineered mice, Mueller created mice with MHC class I molecules on blood and immune system cells but missing from other cells such as nerve cells and connective tissue. LCMV infects both cells that come from bone marrow and cells that don't. But the roles each type of cell plays in communicating the infection to the immune system is different.
"We were trying to sort out which of several factors contribute to T cell exhaustion, such as viral antigen, inflammation and where the immune system encounters the virus," Mueller says. "What came out of these experiments allowed us to answer a broad question: the role of antigen in driving exhaustion."
When injected with LCMV, the altered mice had more energetic and responsive T cells early during the infection. But later, the altered mice had much higher levels of virus and more exhausted T cells. This contrast demonstrates how the level of antigen present is the motor behind immune exhaustion during the chronic infection.
"Early on, the T cells were healthier because they saw less antigen, and only saw it on cells that came from bone marrow," Mueller says. "But later, the immune system had trouble getting rid of the virus because the T cells couldn't recognize infection in cells that were not able to present the viral antigens."
The research was supported by the National Institutes of Health and the Gates Foundation.
The Robert W. Woodruff Health Sciences Center of Emory University is an academic health science and service center focused on missions of teaching, research, health care and public service. Its components include the Emory University School of Medicine, Nell Hodgson Woodruff School of Nursing, and Rollins School of Public Health; Yerkes National Primate Research Center; Emory Winship Cancer Institute; and Emory Healthcare, the largest, most comprehensive health system in Georgia. Emory Healthcare includes: The Emory Clinic, Emory-Children's Center, Emory University Hospital, Emory University Hospital Midtown, Wesley Woods Center, Emory University Orthopaedics & Spine Hospital, the jointly owned Emory-Adventist Hospital, and EHCA, a limited liability company created with Hospital Corporation of America. EHCA includes two joint venture hospitals, Emory Eastside Medical Center and Emory Johns Creek Hospital. The Woodruff Health Sciences Center has a $2.3 billion budget, 18,000 employees, 2,500 full-time and 1,500 affiliated faculty, 4,300 students and trainees, and a $5.5 billion economic impact on metro Atlanta.
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