In a surprising outcome that overturns the conventional wisdom on the body's immune response to infection, scientists at The Scripps Research Institute have shown that T cells do not begin proliferation until up to three days after infection.
Until now, it was generally believed that memory T cells, lymphocytes that recognize pathogens from previous infections, begin cell division at a far earlier point than naïve T cells, fresh cells that respond to new infections. The new findings suggest that the delay may be an evolutionary safeguard against the possible risk of an autoimmune response from an explosive proliferation of T cells.
"It was thought that memory T cells responded more effectively to infection by starting cell division earlier than naïve cells and by multiplying more rapidly after that," said Scripps Research Professor Lindsay Whitton. "Our study shows that neither assumption is true. Even though memory cells detected and responded to virus infection within a few hours, they did not begin to divide until after a lengthy delay. After that, cell division was rapid for both naïve and memory cells."
Nonetheless, Whitton noted that while proliferation of naïve and memory cells are equally delayed, once proliferation began, there was a more robust accumulation of memory cells, possibly as a result of their greater abundance prior to infection.
Whitton and his colleagues used transgenic animal models to trace the proliferation of CD4+ and CD8+ memory T cells. CD8+ cells, also known as cytotoxic T cells, attack infected cells and may be involved in transplant rejection; CD4+ cells help regulate the immune system's response to pathogens such as viruses and bacteria.
"The principal conclusions from our study are that, in a virus-infected animal, both naïve and memory CD4+ T cells show a similar and extended delay of approximately 72 hours before they begin to divide," Whitton said, "and that this is true in both lymphoid and non-lymphoid tissues. This delay occurred despite the fact that the viral antigen reached T cell-stimulatory levels within six to twelve hours after infection."
Importance of Memory
Despite all the advances in the field, Whitton said, no one yet understands precisely how memory T cells work.
"We were very much surprised by the discovery that memory cells didn't begin proliferation sooner than their naïve counterparts," Whitton said. "Memory T cells are central to the protective immunity of infections and vaccinations because they act against subsequent encounters with specific microorganisms. Compared to naïve cells, memory T cells can be triggered by lower antigen levels, and their initial response to infection, such as the production of cytokines, is more rapid and more effective."
The study's in vivo data supported recent in vitro findings, which showed that naive and memory T cells initiate cell division at approximately the same time.
"While other studies have indicated a lag in antigen-driven and antigen-independent T cell proliferation, we show definitively that this lag occurs in vivo and within the context of a live systemic virus infection," Whitton said.
Given that CD8+ and CD4+ T cells are essential for eliminating most viral infections, what would be the benefit of delaying T cell division?
Whitton suggests several possibilities.
"Perhaps the expression of initial response functions and cell division are mutually exclusive," he said. "Immediate cell division might stop memory cells from expressing their cytokines, which could prevent early control of the infection. Alternatively, by delaying the expansion of memory cells, the immune system may ensure the diversification of a microbe-specific T cell response. Such diversification would, presumably, be helpful in combating microbial mutations that inevitably emerge."
The study also suggested that the delay represents an opportunity for the body to gain quick control of the infection by its front-line innate immune response, which is immediate but non-specific. This could then allow memory cell division to take place in a relatively non-inflammatory environment, limiting proliferation. If the immune system's early attempt to control the infection failed, then the body's adaptive immune response could kick in. In this case, T cell division would begin in a more pro-inflammatory environment, driving T cell response to much higher and more effective levels.
"In this way, the T cell response escalates when the infection cannot be resolved within the first few days," Whitton said. "Given that T cells are capable of such dramatic proliferation, this mechanism may reduce the risk of unwanted immunopathology, including autoreactive T cell responses."
The study was published in the April 10, 2008 edition of the online journal Public Library of Science Pathogens (PLoS Pathogens). Other authors of the study, Tentative T Cells : Memory Cells Are Quick to Respond, But Slow to Divide, include Jason K. Whitmire and Boreth Eam of The Scripps Research Institute.
The study was supported by the National Institutes of Health.
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