The Journal of Experimental Medicine
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Published 19 July 2004. doi:10.1084/jem.20031975
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 2, 159-168
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A Role for Thymic Stromal Lymphopoietin in CD4+ T Cell Development

Amin Al-Shami1, Rosanne Spolski1, John Kelly1, Terry Fry2, Pamela L. Schwartzberg3, Akhilesh Pandey4, Crystal L. Mackall2, and Warren J. Leonard1

1 Laboratory of Molecular Immunology, 2 Pediatric Oncology Branch, National Cancer Institute, and 3 The National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892
4 McKusick-Nathans Institute of Genetic Medicine, John Hopkins University, Baltimore, MD 21287

Address correspondence to Warren J. Leonard, Laboratory of Molecular Immunology, Building 10, Room 7N252, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892. Phone: (301) 496-0098; Fax: (301) 402-0971; e-mail: wjl{at}helix.nih.gov

Thymic stromal lymphopoietin (TSLP) signals via a receptor comprising the interleukin (IL)-7 receptor {alpha} chain and a distinctive subunit, TSLP receptor (TSLPR), which is most related to the common cytokine receptor {gamma} chain, {gamma}c. We have generated TSLPR knockout (KO) mice and found that although these mice had normal lymphocyte numbers, {gamma}c/TSLPR double KO mice had a greater lymphoid defect than {gamma}c KO mice. This indicates that TSLP contributes to lymphoid development and accounts for some of the residual lymphoid development in {gamma}c KO mice and presumably in patients with X-linked severe combined immunodeficiency. Injection of TSLP into {gamma}c KO mice induced the expansion of T and B cells. Moreover, sublethally irradiated TSLPR KO mice showed weaker recovery of lymphocyte populations than wild-type (WT) littermates, even when neutralizing anti–IL-7 antibodies were injected. Interestingly, TSLP preferentially stimulated the proliferation and survival of CD4+ single positive thymocytes and peripheral T cells in vitro. Additionally, CD4+ T cells from TSLPR KO mice expanded less efficiently than WT CD4+ T cells in irradiated hosts, and TSLP preferentially expanded CD4+ T cells both in vitro and in vivo. Thus, as compared with other known cytokines, TSLP is distinctive in exhibiting a lineage preference for the expansion and survival of CD4+ T cells.

Key Words: thymocyte development • IL-7 • SCID • CD8 T cells • knockout mice

The online version of this article contains supplemental material.

Abbreviations used in this paper: BrdU, 5-bromo-2'-deoxyuridine; CFSE, carboxyfluorescein succinimidyl ester; DKO, double KO; DN, double negative; DP, double positive; ES, embryonic stem; SP, single positive; TSLP, thymic stromal lymphopoietin.


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