|Researchers Identify New Regulatory Circuit
Controlling Immune Cell Production in Mice
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
"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
Dendritic cells are a specialized type of white blood cells that
can potently induce T cell activation, and some of these cells
contain cell surface proteins that act as receptors for IL-7. Mackall's
team also found that interruption of IL-7-induced signaling in
these dendritic cells led to an increase in CD4+ T cell proliferation.
Cell signaling is a biochemical pathway that regulates cellular
functions, such as proliferation or survival. The researchers say
that this finding identifies a new regulatory circuit that prevents
uncontrolled CD4+ T cell proliferation in mice.
"This work in mice may provide an answer to a clinical problem
that has been recognized for some time, but has had no reasonable
mechanistic basis for understanding," said Mackall. "It
also points out the intricacies of regulatory biology in general
and IL-7 biology in particular, since IL-7 has not previously been
implicated in turning off immune reactions, but rather serving
as an immune stimulant. This work provides a counterpoint to considering
IL-7 solely as an immune stimulator."
For more information on Dr. Mackall's research, please go to http://ccr.cancer.gov/staff/staff.asp?profileid=5595.
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Guimond M, Veenstra RG, Grindler DJ, Zhang H, Cui Y, Murphy RD, Kim Y, Na R, Hennighausen L, Kurtulus S, Erman B, Matzinger P, Merchant MS, and Mackall CL. Interleukin 7 signaling in dendritic cells regulates the homeostatic proliferation and niche size of CD4+ T cells. Nature Immunology. Online January 11, 2009.