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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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Submitted February 6, 2008
Accepted July 4, 2008
Development of regulatory T cells requires IL-7R stimulation by IL-7 or TSLP
Renata Mazzucchelli, Julie A Hixon, Rosanne Spolski, Xin Chen, Wen Qing Li, Veronica L. Hall, Jami Willette-Brown, Arthur A Hurwitz, Warren J Leonard, and Scott K Durum*
Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, NCI, Frederick, MD, United States
Laboratory of Molecular Immunology, NHLBI, Bethesda, MD, United States
Basic Research Program, SAIC-Frederick, Inc., Frederick, MD, United States
Laboratory of Experimental Immunology, Cancer and Inflammation Program, NCI, Frederick, MD, United States
* Corresponding author; email: durums{at}mail.ncifcrf.gov.
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 two 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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