AIDSWEEKLY Plus; Monday, April 6, 1998
Daniel J. DeNoon, Senior Editor
Astonishing new findings show that the size of the initial immune response to a virus determines the strength of long-term immunity.
"These findings have clear implications for developing strategies to improve vaccines," stated Kaja Murali-Krishna, John D. Altman, Rafi Ahmed, and colleagues at the Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia. "They show that the size of the memory T-cell pool is determined by the original burst size and emphasize the importance of initial priming in inducing long-term immunity."
Murali-Krishna et al. reported the findings in the journal Immunity ("Counting Antigen-Specific CD8 T Cells: A Reevaluation of Bystander Activation during Viral Infection," Immunity, 1998; 8:177- 87).
The results of their studies completely reverse current beliefs about how T cells become activated. These beliefs - orthodoxy until now - held that only a very small proportion of activated CD8(+) T cells are specific to viral antigens during the peak of primary immune responses to viral infection.
Murali-Krishna et al. show that these estimates must drastically be revised: instead of only 1 to 5 percent, more than 70 percent of activated CD8(+) T cells are specific for viral antigens.
These amazing new results come from the use of a direct assay to visualize antigen-specific cells. The assay uses tetrameric MHC class I molecules loaded with viral peptides that bind and mark for visualization virus-specific cells in sera obtained during acute viral infection. The model used in the current studies was lymphocytic choriomeningitis virus (LCMV) infection of mice.
This direct assay corrected a flaw inherent in the limiting dilution assays (LDA) upon which previous estimates were based. The LDA requires culturing cells at various dilutions and then stimulating them for up to two weeks with interleukin 2 (IL-2). Only cells that can divide and survive this stimulation period can be counted.
Murali-Krishna et al. took notice of evidence that activated T cells - the very cells that must be counted for evaluation of the dynamics of antiviral immunity - tend to die during restimulation via the process of programmed cell death or apoptosis (Nagata, S. and Goldstein, P.; Science, 1995;267:1449-56). They therefore employed the new assay, which does not require restimulation of activated cells.
"It is likely that our study in the LCMV system, showing that more than 70 percent of the responding CD8(+) T cells are virus specific, will become a paradigm for viral infections in general," they wrote.
Once a virus is cleared, apoptosis deletes more than 90 percent of activated T cells, thereby maintaining T-cell homeostasis. The remaining virus-specific cells are added to the pool of memory cells.
Murali-Krishna et al. used their assay to explore whether cells recognizing dominant viral epitopes are more likely to survive apoptosis than those recognizing subdominant epitopes.
"For each of the peptide-specific responses, approximately 5 percent of the activated CD8(+) T cells survived and went into the pool of memory T cells, and then long-term memory was equally well maintained for both strong and weak epitopes," they reported.
The two data sets have important implications. They strongly suggest that antiviral vaccines can be effective only when they elicit strong initial responses. Weak responses are unlikely to be much improved by subsequent boosts.
"Together these results show that the difference between a strong response and a weak response was not in the death phase nor in the maintenance of memory but was determined by the original burst size," Murali-Krishna et al. wrote. "This greatly revises our current thinking on the dynamics of T-cell activation in vivo and warrants a reexamination of the prevailing models of viral-induced T-cell proliferation."
This work was supported by National Institutes of Health grants AI 30047 and NS 21496 and by an American Cancer Society Institutional Research grant and support from the Winship Cancer Center of Emory University.
The corresponding author for this study is Rafi Ahmed, Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia 30322. Email: <ra@microbio.emory.edu>.
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