Researchers at Washington University School of Medicine in St. Louis have discovered how to grow a little-understood type of human immune cell. The cells, known as T-regulatory cells type 1 (Tr1), are thought to turn off unnecessary immune reactions and to block the action of immune cells that otherwise would attack the body and cause dangerous inflammation. The findings are reported in the Jan. 23 issue of the journal Nature.

“T-regulator cells have become an important area of immunology,” says John P. Atkinson, M.D., the Samuel B. Grant Professor of Medicine and professor of molecular microbiology, who led the study. “But no one has known how to grow them in the laboratory. These findings will let that promising research move forward.”

Research using laboratory-grown Tr1 cells could lead to new treatments for autoimmune diseases such as lupus and rheumatoid arthritis and for organ rejection following transplantation, and could provide a better understanding of measles, meningitis and other infectious diseases.

“We now can take a blood sample from someone’s arm, culture selected cells from that sample and a few days later have a nice population of T-regulatory cells,” says first author Claudia Kemper, Ph.D., a postdoctoral fellow in Atkinson’s laboratory. “To be able to manipulate the activity of Tr1 cells for future therapeutic use relies heavily on knowing the factors required for their differentiation and function.”

In 1985, Atkinson’s team discovered a protein known as CD46 on cell surfaces. Usually this protein protects cells from being destroyed by a component of the immune system known as complement.

In this study, Kemper and her colleagues found that stimulating CD46 and a second cell-surface molecule known as T-cell receptor caused certain kinds of immune cells called T lymphocytes to grow, divide and give off a substance known as interleukin-10 (IL-10).

The team established the finding by growing Tr1 cells in culture dishes for several days, drawing off some of the fluid bathing the cells and adding that fluid to other dishes containing activated, proliferating infection-fighting T cells. The fluid, which contained IL-10 produced by the Tr1 cells, shut down the growth and activity of the T cells.

“That was a very good day,” says Kemper. “IL-10 is the classic substance that suppresses the action and proliferation of other immune cells.”

The investigators next want to study how CD46 triggers production of IL-10 and to better define the population of cells that give rise to Tr1 cells. They also want to explore how viruses, including those that cause measles, meningitis and herpes, interact with CD46.

“It’s tempting to think that these pathogens dock with CD46 because it causes some cells to produce IL-10, which would suppress the action of nearby immune cells and help the pathogen survive,” says Kemper. “We can investigate such questions because we can now grow these cells in the laboratory.”

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Kemper C, Chan AC, Green JM, Brett KA, Murphy KM, Atkinson JP. Activation of human CD4+ cells with CD3 and CD46 induces a T-regulatory cell 1 phenotype. Nature, Jan. 23, 2003.

Funding from the National Institute of Allergy and Infectious Diseases supported this research.

The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.

Contact: Darrell E. Ward, wardd@msnotes.wustl.edu, 314-286-0122, Washington University School of Medicine

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