A role for IL-7 in regulating CD4⁺CD25^high regulatory T cells

Background

Despite the accumulation of evidence that CD4⁺CD25^high regulatory T cells play an important role in the prevention of autoimmune disease, little is known about how they are regulated in vivo. There are thought to be at least two mechanisms for the generation of regulatory T cells: naturally occurring CD4⁺CD25^high regulatory T cells derive from the thymus, and peripherally-induced regulatory cells arise under tolerogenic conditions. Recently, cytokine activation requirements for CD4⁺CD25^high regulatory T-cell function were associated with IL-7, as well as IL-2 and IL-4. We examined a cohort of patients with rheumatoid arthritis whose disease was well controlled, and where we had previously shown that heterogeneous circulating levels of IL-7 positively correlated with thymic activity, to investigate the role of IL-7 on the function of CD4⁺CD25^high T cells.

Methods

Peripheral blood samples were taken from patients with rheumatoid arthritis whose disease was well controlled. Serum IL-7 levels were measured by ELISA. Quantification of the CD4⁺CD25^high T-cell subset was performed using flow cytometry. Thymic activity was evaluated by real-time PCR quantification of T-cell receptor excision circles in CD4⁺ T cells. Thymidine incorporation assays were used to assess the response of CD4⁺CD25^high T cells to IL-7 stimulation, and also their ability to suppress the proliferation of CD4⁺CD25^- T cells in response to phytohaemagglutinin in co-culture.

Results

Circulating levels of IL-7 positively correlated with the frequency of circulating CD4⁺CD25^high T cells (n = 47, R = 0.647, P < 0.0001). This appeared to result from an increased production of these cells by the thymus. High levels of circulating IL-7 in vivo were associated with increased suppressor functions of CD4⁺CD25^high T cells in vitro (n = 5, mean 79% suppression by cells from patients with high IL-7 levels, and 39% suppression by cells from patients with low IL-7 levels). In patients with low circulating IL-7 levels, adding exogenous IL-7 to co-cultures appeared to increase suppression.

Conclusions

Our data suggest that IL-7 has a role in regulating CD4⁺CD25^high T-cell number and function. Circulating IL-7 levels are low in active rheumatoid arthritis, and this may be a contributory factor to the reduced size and suppressor function of the CD4⁺CD25^high regulatory T-cell population in this disease.