Interleukin 7 signaling in dendritic cells regulates the homeostatic proliferation and niche size of CD4+ T cells

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Abstract

Interleukin 7 (IL-7) and T cell antigen receptor signals have been proposed to be the main drivers of homeostatic T cell proliferation. However, it is not known why CD4+ T cells undergo less-efficient homeostatic proliferation than CD8+ T cells do. Here we show that systemic IL-7 concentrations increased during lymphopenia because of diminished use of IL-7 but that IL-7 signaling on IL-7 receptor-α–positive (IL-7Rα+) dendritic cells (DCs) in lymphopenic settings paradoxically diminished the homeostatic proliferation of CD4+ T cells. This effect was mediated at least in part by IL-7-mediated downregulation of the expression of major histocompatibility complex class II on IL-7Rα+ DCs. Our results indicate that IL-7Rα+ DCs are regulators of the peripheral CD4+ T cell niche and that IL-7 signals in DCs prevent uncontrolled CD4+ T cell population expansion in vivo.

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Figure 1: IL-7Rα signaling regulates stromal IL-7 production in vivo.
Figure 2: High systemic concentrations of IL-7 'preferentially' expand CD8+ but not CD4+ T cell populations.
Figure 3: Bone marrow–derived IL-7 supports the homeostatic proliferation of CD4+ T cells in lymphopenic hosts, whereas stromal cell-derived IL-7 inhibits this proliferation.
Figure 4: IL-7 signaling on bone marrow–derived cells inhibits the homeostatic proliferation of CD4+ T cells during lymphopenia.
Figure 5: IL-7 signaling diminishes the expression of MHC class II on APCs during lymphopenia.
Figure 6: Stromal cell–derived IL-7 regulates DC IL-7 production in the lymphoid microenvironment.
Figure 7: IL-7 acts directly on CD4+ T cells.

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Acknowledgements

We thank V. Kapoor and N. Voong for flow cytometry expertise; M.A. Caligiuri (Ohio State University) for Flt3 ligand; S. Durum (National Cancer Institute) for Rag1−/−Il7−/− mice; and S. Durum, A. Singer and R. Gress for review of the manuscript. Supported by the Intramural Program of the National Cancer Institute.

Author information

M.G. did most of the experiments, contributed to experimental design and wrote the manuscript; R.G.V., D.J.G. and R.D.M. did experiments; H.Z. did experiments and provided intellectual input; Y.C. did experiments, generated Stat5a−/−Stat5b−/− mice and provided intellectual and technical input; S.Y.K. provided technical support for immunofluorescence studies; R.N. bred and genotyped Stat5a+/−Stat5b+/− mice and provided fetal livers; L.H. provided Stat5a+/−Stat5b+/− mice and intellectual input; P.M. provided intellectual input and transgenic mice; B.E. provided intellectual input and generated and provided GFP–IL-7Rα mice; M.S.M. did experiments and provided intellectual input; and C.L.M. provided intellectual input and research support and contributed to writing the manuscript.

Correspondence to Crystal L Mackall.

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