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Blood, 15 October 2008, Vol. 112, No. 8, pp. 3283-3292.
Prepublished online as a Blood First Edition Paper on July 29, 2008; DOI 10.1182/blood-2008-02-137414.
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IMMUNOBIOLOGY
Development of regulatory T cells requires IL-7R stimulation by IL-7 or TSLP
Renata Mazzucchelli1,
Julie A. Hixon1,
Rosanne Spolski2,
Xin Chen3,
Wen Qing Li1,
Veronica L. Hall4,
Jami Willette-Brown1,
Arthur A. Hurwitz1,
Warren J. Leonard2, and
Scott K. Durum1
1 Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Frederick, MD;
2 Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD;
3 Basic Research Program, SAIC-Frederick, NCI-Frederick, MD; and
4 Laboratory of Experimental Immunology, Cancer and Inflammation Program, Center for Cancer Research, NCI, NIH, Frederick, MD
Interleukin-7 (IL-7), a cytokine produced by stromal cells, is required for thymic development and peripheral homeostasis of most major subsets of T cells. We examined whether regulatory T (Treg) cells also required the IL-7 pathway by analyzing IL-7R –/– mice. We observed a striking reduction in cells with the Treg surface phenotype (CD4, CD25, GITR (glucocorticoid-induced tumor necrosis factor [TNF]-like receptor), CD45RB, CD62L, CD103) or intracellular markers (cytotoxic T-lymphocyte–associated antigen-4, CTLA-4, and forkhead box transcription factor 3, Foxp3). Foxp3 transcripts were virtually absent in IL-7R–/– lymphoid tissues, and no Treg cell suppressive activity could be detected. There are 2 known ligands for IL-7R: IL-7 itself and thymic stromal lymphopoietin (TSLP). Surprisingly, mice deficient in IL-7 or the other chain of the TSLP receptor (TSLPR) developed relatively normal numbers of Treg cells. Combined deletion of IL-7 and TSLP receptor greatly reduced Treg cell development in the thymus but was not required for survival of mature peripheral Treg cells. We conclude that Treg cells, like other T cells, require signals from the IL-7 receptor, but unlike other T cells, do not require IL-7 itself because of at least partially overlapping actions of IL-7 and TSLP for development of Treg cells.
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[Abstract]
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