Development of regulatory T cells requires IL-7Ralpha stimulation by IL-7 or TSLP.
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-7Ralpha(-/-) 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-7Ralpha(-/-) lymphoid tissues, and no Treg cell suppressive activity could be detected. There are 2 known ligands for IL-7Ralpha: 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.
Mazzucchelli
Renata
R
Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Frederick, MD, USA.
Hixon
Julie A
JA
Spolski
Rosanne
R
Chen
Xin
X
Li
Wen Qing
WQ
Hall
Veronica L
VL
Willette-Brown
Jami
J
Hurwitz
Arthur A
AA
Leonard
Warren J
WJ
Durum
Scott K
SK
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002469:Cell Separation; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D015851:Interleukin-7 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D020395:Receptors, Interleukin-7 / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology; D000094632:Thymic Stromal Lymphopoietin
D016207:Cytokines; D015851:Interleukin-7; D020395:Receptors, Interleukin-7; C415350:interleukin-7 receptor, alpha chain; D000094632:Thymic Stromal Lymphopoietin; C000721967:TSLP protein, mouse