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IL-15 Is Required for Sustained Lymphopenia-Driven Proliferation and Accumulation of CD8 T Cells¹

Michelle M. Sandau^*,, Colleen J. Winstead^*, and Stephen C. Jameson^2,*,,

^* Center for Immunology, Department of Laboratory Medicine and Pathology, Department of Medicine, and Cancer Center University of Minnesota, Minneapolis MN 55455

Naive T cells undergo slow homeostatic proliferation in response to T cell lymphopenia, which is also called lymphopenia-induced proliferation (LIP). IL-7 is critically required for this process, but previous studies suggested IL-15 was expendable for LIP of naive CD8 T cells. In contrast, we show that IL-15 is important for sustained CD8 T cell proliferation and accumulation in a lymphopenic setting, as revealed by truncated LIP in IL-15^–/– hosts. At the same time, we find that IL-12 enhances LIP by acting directly on the CD8 T cells and independently of IL-15, suggesting distinct pathways by which cytokines can regulate homeostatic proliferation. Interestingly, the memory-phenotype CD8 T cell generated by LIP in IL-15^–/– hosts are phenotypically distinct from the rare endogenous memory-phenotype cells found in IL-15^–/– animals, suggesting these cells are generated by different means. These findings demonstrate that cytokine requirements for LIP change during the process itself, illustrating the need to identify factors that regulate successive stages of lymphopenia-driven proliferation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant R37 AI38903 by the National Institutes of Health (to S.C.J.) and by an Immunology Predoctoral Training Grant T32 AI07313 (to M.M.S.).

² Address correspondence and reprint requests to Dr. Stephen C. Jameson, Center for Immunology, University of Minnesota Medical School, Mayo Mail Code 334, 420 Delaware Street SE, Minneapolis MN 55455. E-mail address: james024{at}umn.edu

³ Abbreviations used in this paper: LIP, lymphopenia-induced proliferation; WT, wild type.