BioWorld International Correspondent
LONDON - A glimpse of the secret life of the cytotoxic T cell has suggested new ways of making vaccination more efficient and revealed a potential strategy for boosting the immune systems of people infected with the human immunodeficiency virus, as well as others with immunodeficiency disorders.
A team of French researchers at the Institut Necker in Paris reported a series of experiments that provides fresh insights into the mechanism underlying activation of CD8+ T cells. Their paper appears in the Sept. 20, 2002, issue of Science. Its title is "A role for CD40 Expression on CD8+ T Cells in the Generation of CD8+ T Cell Memory."
Corinne Tanchot, researcher at INSERM at the Institut Necker, told BioWorld International, "This finding could have important implications for vaccination in any circumstances, to boost or create a very efficient memory population. Any vaccine which is not very efficient at the moment could be improved with the help of the strategy that our work suggests."
Tanchot and colleagues Christine Bourgeois and Benedita Rocha, also of the Institut Necker, wanted to understand the processes by which CD8+ T cells, also known as cytotoxic T cells, become activated by an antigen, thus generating a population of memory cells that are primed to respond more efficiently to the same antigen in the future.
CD8+ T cells are the key mediators of the cellular immune response, which is involved in fighting infection by viruses and intracellular pathogens such as Mycobacterium tuberculosis. Researchers, however, have found it difficult to work out how to stimulate that arm of the immune response when designing vaccines. If they could solve that problem, vaccines to protect against many diseases would be a lot closer.
The team worked with female transgenic mice that had been genetically manipulated to express a receptor molecule on the surface of their CD8+ T cells that could be specifically stimulated by the male histocompatibility antigen (HY). Isolated from the mice, those CD8+ T cells can be infused into female mice that lack T cells. If the female mice are injected with cells from male mice, the transgenic CD8+ T cells will eliminate the male cells.
Tanchot and her colleagues tried injecting the transgenic CD8+ T cells with and without CD4+ T cells in female mice previously injected with the male antigen. After two months, they looked for memory T cells. They found that CD4+ T cells seemed to be crucial for the CD8+ T cells to develop into efficient memory cells.
"Our experiments showed that CD4+ T cells help to increase the expansion of CD8+ T cells and increased their secretion of cytokines," Tanchot said.
They then wanted to try to find out the mechanism that mediated this help. Other groups had proposed, Tanchot said, that the help was of an indirect nature. "The hypothesis was that the CD40 ligand on CD4+ T cells would interact with CD40 molecules on antigen-presenting cells, which would then activate the CD8+ cells," Tanchot said. "We decided to test this hypothesis, and were able to conclude that the expression or absence of CD40 on antigen-presenting cells played no role whatsoever in the ability of CD4+ T cells to help activate CD8+ T cells."
The team was surprised by the finding. They decided to examine if CD8+ T cells themselves could express the CD40 molecule. "We found that they could," Tanchot said. "This is the very new discovery reported in this paper - that expression of CD40 on CD8+ T cells allows them to receive CD4+ T cell help and to differentiate very efficiently into memory cells."
One application of the finding could be to boost or restore CD8+ T-cell responses in conditions, such as HIV infection, where the cells fail to respond normally. "It might be possible to do this by injecting anti-CD40 antibodies," Tanchot said. "In addition, with any vaccine that is not very efficient, or where its efficiency would benefit from improvement, including such antibodies in the vaccination, it could improve it."
The group now plans to use a technique called multiplex RT-PCR, which it developed a year ago, to tease out which genes are switched on during CD8+ T cell activation. "This technology allows us to study up to about 20 genes simultaneously in the same cell, and determine whether they are expressed or not. So we can compare the expression of genes in CD8+ T cells that have CD40 with that of CD8+ T cells that have no CD40," Tanchot said. "We hope to find a difference, and if we do, we should be able to produce a program of differentiation for a CD8+ memory T cell that will tell us all the genes involved in its becoming a memory cell."