A team of Canadian and Finnish scientists has identified a protein able to stimulate the production of T-cells, the white blood cells involved in the recognition and the elimination of infectious agents. The discovery by researchers of the Institute for Research in Immunology and Cancer (IRIC) at the Université de Montréal in Canada and the University of Oulu in Finland - published in the latest edition of the journal Immunity - could help to combat age-related declines in immune response.
Thanks to the work of Dr. Claude Perreault and his team, which identified the properties of a protein called Wnt4, it is now possible to envision news ways to reverse the age-related decline of the immune system. "Thymic atrophy is a major public health problem," said Dr. Perreault.
"It compromises the efficacy of vaccination and weakens the resistance to common viruses, for instance to the respiratory syncytial virus (RSV), which is responsible each year for the hospitalization of more than 150,000 people in the U.S. This is due to the fact that 'old' T cells are not equipped to face the threat of new foreign bodies, whether they are viruses or tumours."
The atrophy of the thymus, a small gland at the base of the neck where T cells mature, is one of the most obvious signs of the age-related decline of the immune system. This decline becomes significant towards the age of 50. It is caused not only by a decreased output of T cells from the thymus, but also by a decreased ability to recognize new antigens. The result is an increased susceptibility to infection as well as a lowered resistance to the immunosuppressive effects of chemotherapy.
Wnt4 protein stimulates white blood cells
By inducing an overproduction of the Wnt4 protein in the cells of the mouse immune system, Dr. Perreault and his collaborators were able to observe the stimulatory effect this protein exerts on the development of white blood cells. Using molecular markers that are specific to the different stages of cell maturation, IRIC researchers determined that elevated levels of Wnt4 led to a marked increase in the number of white blood cell progenitors, and of immature T cells in the thymus in particular.
Conversely, they found that deletion of the Wnt4 gene and lack of the corresponding protein was associated with a decrease in the number of T cell progenitors in the thymus.
After showing that Wnt4 could stimulate thymopoiesis, the name given to the production of T cells in the thymus, Dr. Perreault and his team sought to understand the mode of action of the protein. Isabelle Louis, a graduate student, and Dr. Krista Heinonen, a postdoctoral fellow, analyzed the changes in gene activity triggered by exposure to
Wnt4. Results were conclusive: Wnt4 increases the number of T cell progenitors by inducing the expression of genes involved in cell survival. IRIC researchers also showed that Wnt4 does not mediate these changes in gene expression through the intracellular pathway normally activated by members of the Wnt family, i.e. stabilization of a signalling protein called -catenin, but rather through an alternative pathway involving members of the JNK family of proteins. The IRIC team is now investigating ways to capitalize on its discovery to develop new therapeutic agents.
About the study: "The Signaling Protein Wnt4 Enhances Thymopoiesis and Expands Multipotent Hematopoietic Progenitors through β-Catenin-Independent Signaling," was published in the journal Immunity (July 18, 2008 issue, vol. 29, pp. 57-67). Collaborators include Isabelle Louis, Dr. Krista M. Heinonen, Dr. Jalila Chagraoui, postdoctoral fellow at IRIC and Dr. Seppo Vainio from the University of Oulu in Finland also co-signed the article, which is entitled was conducted with a team led by Dr. Guy Sauvageau, director of the Molecular Genetics of Stem Cells Laboratory at IRIC.
Partners in research: The research was funded by the Canadian Institutes of Health Research and the National Cancer Institute of Canada.