Researchers Identify IL-7 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 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.
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
NCI leads the National Cancer Program and the NIH effort to dramatically reduce the burden of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI Web site at http://www.cancer.gov or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
The National Institutes of Health (NIH) - The Nation's Medical Research Agency - includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
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.
AIDS:Volume 21(8)11 May 2007p 1048-1050
Relationship between serum IL-7 concentrations and lymphopenia upon different levels of HIV immune control
Fluur, Carolinea; Rethi, Bencea; Thang, Pham Honga,b; Vivar, Nancya; Mowafi, Fridaa; Lopalco, Luciac; Foppa, Caterina Ubertic; Karlsson, Andersd; Tambussi, Giuseppec; Chiodi, Francescaa
aDepartment of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
bHIV/AIDS Department, National Institute of Hygiene and Epidemiology, Hanoi, Vietnam
cInfectious Disease Clinic, San Raffaele Scientific Institute, Milan, Italy
dVenhalsan, Department of Infectious Diseases, Karolinska University Hospital, Stockholm._
High levels of IL-7 are associated with CD4 T-cell depletion in HIV-1 infection [1-4]. IL-7 is an essential factor for T-cell differentiation and survival [5,6], and a high IL-7 concentration has been proposed as a mechanism that may promote T-cell regeneration through increased survival and proliferation [4,7,8]. The negative correlation observed between CD4 T-cell counts and serum IL-7 levels [1-4] raises the question of whether IL-7 is able to promote T-cell regeneration, or alternatively, serum IL-7 levels passively increase when the T cells consuming IL-7 are depleted without IL-7 being beneficial on T-cell homeostasis. IL-7 accumulation and the decreased efficiency of IL-7 on T-cell survival might be accelerated by the IL-7R_ downregulation observed on T cells in correlation with increased serum IL-7 levels during HIV-1 infection [9,10]. Increased IL-7 levels have also been reported during primary HIV-1 infection [10,11], probably as a result of early T-cell depletion. Baseline IL-7 levels correlated with CD4 T-cell recovery after primary infection suggesting, in contrast to chronic infection, a positive role for IL-7 on T-cell restoration during the early phase of HIV-1 infection .
In this study we analysed the relationship of variations in serum IL-7 levels and T-cell numbers occurring upon disease progression in treatment-naive, HIV-infected individuals, and we also studied whether IL-7 might play a role in T-cell maintenance in long-term non-progressors (LTNP). Serum IL-7 concentrations were determined by the Quantikine high sensitivity immunoassay (R&D Systems, Minneapolic, Minnesota, USA) according to the manufacturer's recommendations.
High IL-7 levels were observed in blood specimens from HIV-infected patients with CD4 T-cell counts less than 200 cells/μl, whereas most patients with CD4 T-cell counts above this number were characterized by lower IL-7 concentrations [1-4]. In these previously analysed cohorts CD4 T-cell counts were positively influenced by antiretroviral therapy (ART), which might confound the natural regulation of the IL-7 level during HIV-1 infection. In order to exclude a possible effect of ART on IL-7 levels, we analysed the alteration of IL-7 levels in treatment-naive, chronically HIV-1-infected individuals (n = 19), followed between 1983 and 1987 at the Karolinska University Hospital in a study period ranging between 13 and 56 months. Serum samples were taken at two to four different time-points from each individual. In this cohort of untreated patients, when including all measurements, we could not find a correlation between IL-7 levels and CD4 T-cell counts (Fig. 1a,d). IL-7 levels showed, however, a negative correlation with CD8 (Fig. 1b,d) and CD3 T-cell counts (Fig. 1c,d), indicating the potential role of T-cell lymphopenia in the increase in serum IL-7 in drug-naive individuals. We did not detect any correlation between IL-7 levels and the change in T-cell numbers in the following period, indicating that IL-7 might be inefficient in improving T-cell numbers during the late phase of HIV-1 infection (Fig. 1d).
We further analysed samples collected longitudinally from the same individuals to assess whether IL-7 levels passively follow alterations of CD4 and CD8 T-cell numbers or if the high IL-7 concentration can play a feedback role in improving T-cell numbers, at least in some individuals. In some patients, increased IL-7 levels were associated with decreasing CD4 T-cell counts (Fig. 1e, patients 1, 2, 3, 8) and CD8 T-cell counts (Fig. 1e, patients 2, 3, 8), according to the trend suggested by the inverse correlation between IL-7 levels and T-cell counts in cross-sectional analyses [1-4]. On the other hand, in other patients, the decrease in IL-7 levels preceded or occurred in parallel with CD4 T-cell depletion (patients 3, 4, 5, 6, 7); also IL-7 downregulation preceded the progression to AIDS in patients 3, 4 and 5. The CD8 T-cell count, in some donors, increased or decreased in parallel with similar changes in IL-7 concentration (patients 1, 4, 5, 7). These latter observations suggest that peripheral T-cell maintenance by high IL-7 levels, possibly occurring in some chronically HIV-1-infected individuals, may collapse before progression to AIDS.
Next we analysed whether IL-7 might play a role in T-cell maintenance in HIV-1-infected LTNP patients, characterized by a CD4 T-cell count of 500 cells/μl or greater and controlled viral replication for 7-10 years in the absence of ART . Serum IL-7 levels were compared in 45 patients from a previously characterized LTNP cohort  and in 16 chronically HIV-1-infected patients with comparable CD4 T-cell counts (> 500 cells/μl) during ART (Fig. 1f). Both cohorts were followed at the San Raffaele Institute, Milan. We could not detect a significant difference between IL-7 concentrations in these two cohorts, suggesting an IL-7-independent T-cell maintenance in LTNP individuals. Twenty of the LTNP patients included in our analysis lost their LTNP status during a 3-year follow-up period . Interestingly, IL-7 levels were significantly lower in individuals with stable LTNP status than in those patients who lost their LTNP status during follow-up (Fig. 1g). Further studies are required in LTNPs to determine whether high IL-7 levels reflect an ongoing T-cell depletion in compartments other than peripheral blood or if IL-7 plays an active role in facilitating viral replication [13-15].
Altogether, our results showed that in chronic HIV-1 infection, increased IL-7 levels are generally observed in parallel with ongoing T-cell depletion, and a possible role of IL-7 in T-cell maintenance is indicated only in sporadic cases. In LTNP a high IL-7 concentration appears to predict accelerated disease progression.
The first two authors contributed equally to this work.
Sponsorship: This study was supported by grants received from the Swedish MRC, the Swedish International Development Agency (SIDA-SAREC) and PHI ISS grant 30F.48. B.R. was supported by the Marie Curie Intra-European Fellowship and the Hungarian State Eotvos Fellowship.
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