Using a mouse model, researchers have shown that elevated levels of a small protein known as interleukin 7 (IL-7) plays a central role in regulating the production of a type of white blood cell that is required for effective immune responses.
This finding helps explain the delayed and incomplete recovery of immune system function after treatments such as chemotherapy and bone marrow transplantation, in which immune cells are destroyed, and provides insight into the mechanism by which certain types of immune cells are depleted during HIV infection. The study, by researchers at the National Cancer Institute (NCI), the National Institute of Diabetes, Digestive, and Kidney Diseases, and the National Institute of Allergy and Infectious Diseases, parts of the National Institutes of Health (NIH), appeared online Jan. 11, 2009, in Nature Immunology.
White blood cells known as T lymphocytes, or T cells, are essential components of the immune system. They can be divided into two major groups: CD4+ T cells, which act as helper cells, directing the activity of other immune cells, and CD8+ T cells, which kill infected cells and tumor cells. The function of the thymus, the organ where T cells differentiate in order to perform specific functions, declines with age. When T cells become depleted in adults, they can undergo spontaneous, or homeostatic, proliferation in an attempt to restore their numbers. Although homeostatic proliferation efficiently regenerates CD8+ T cells, it is much less efficient in regenerating CD4+ T cells.
"Essentially any clinical condition that induces the death of lymphocytes is followed by restoration of CD8+ T cells with chronic long-term deficiency of CD4+ T cells," said study author Crystal Mackall, M.D., of NCI's Center for Cancer Research. "For example, after bone marrow transplantation, patients recover essentially every other type of lymphocyte within six to eight months but the depletion of CD4+ T cells can last years."
Indeed, although CD4+ T cell depletion is the main hallmark of HIV infection, it has remained an enigma why CD8+ T cells are not similarly depleted, given that both CD4+ and CD8+ T cells are killed during the course of the disease. Because CD4+ T cells are the initiators of adaptive immunity, which enables the immune system to recognize and remember pathogens, normal immune system functioning cannot be restored unless CD4+ T cell numbers recover.
IL-7 is a cytokine that is known to play an important role in homeostatic proliferation of T cells. Cytokines are small proteins produced by immune cells that help regulate immune responses. When the level of lymphocytes in the blood is low - a condition known as lymphopenia - concentrations of IL-7 increase. Previous research in humans has indicated that, despite IL-7's role in stimulating homeostatic T cell proliferation, elevated levels of IL-7 may be associated with low CD4+ T cell counts.
To investigate the role of IL-7 in CD4+ T cell homeostasis, the researchers injected T cells labeled with a marker into mice depleted of lymphocytes, and, in a subset of these mice, they also administered laboratory-produced IL-7 to further increase the level of IL-7 in the blood. Using flow cytometry, a laboratory technique that allows researchers to measure the concentrations of different types of cells, they found that, within seven days, most of the CD8+ T cells had divided, but the proliferation of CD4+ T cells was minimal.