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IL-7 Activates the Phosphatidylinositol 3-Kinase/AKT Pathway in Normal Human Thymocytes but Not Normal Human B Cell Precursors¹

Sonja E. Johnson^*, Nisha Shah^*, Anna A. Bajer^* and Tucker W. LeBien^2,*,

^* The Masonic Cancer Center and Department of Laboratory Medicine/Pathology, University of Minnesota Medical School, Minneapolis, MN 55455

IL-7 signaling culminates in different biological outcomes in distinct lymphoid populations, but knowledge of the biochemical signaling pathways in normal lymphoid populations is incomplete. We analyzed CD127/IL-7R expression and function in normal (nontransformed) human thymocytes, and human CD19⁺ B-lineage cells purified from xenogeneic cord blood stem cell/MS-5 murine stromal cell cultures, to further clarify the role of IL-7 in human B cell development. IL-7 stimulation of CD34⁺ immature thymocytes led to phosphorylation (p-) of STAT5, ERK1/2, AKT, and glycogen synthase kinase-3 β, and increased AKT enzymatic activity. In contrast, IL-7 stimulation of CD34^– thymocytes (that included CD4⁺/CD8⁺ double-positive, and CD4⁺ and CD8⁺ single-positive cells) only induced p-STAT5. IL-7 stimulation of CD19⁺ cells led to robust induction of p-STAT5, but minimal induction of p-ERK1/2 and p-glycogen synthase kinase-3 β. However, CD19⁺ cells expressed endogenous p-ERK1/2, and when rested for several hours following removal from MS-5 underwent de-phosphorylation of ERK1/2. IL-7 stimulation of rested CD19⁺ cells resulted in robust induction of p-ERK1/2, but no induction of AKT enzymatic activity. The use of a specific JAK3 antagonist demonstrated that all IL-7 signaling pathways in CD34⁺ thymocytes and CD19⁺ B-lineage cells were JAK3-dependent. We conclude that human CD34⁺ thymocytes and CD19⁺ B-lineage cells exhibit similarities in activation of STAT5 and ERK1/2, but differences in activation of the PI3K/AKT pathway. The different induction of PI3K/AKT may at least partially explain the different requirements for IL-7 during human T and B cell development.

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 the Leukemia Research Fund, the Minnesota Medical Foundation, and the Graduate School (University of Minnesota). S.E.J. was supported by Immunology Training Grant T32 AI07313 and Cancer Biology Training Grant T32 CA01938. T.W.L. is the Apogee Enterprises Chair in Cancer Research.

² Address correspondence and reprint requests to Dr. Tucker W. LeBien, Department of Laboratory Medicine/Pathology and The Cancer Center, University of Minnesota, MMC806, 420 Delaware Street Southeast, Minneapolis, MN 55455. E-mail address: lebie001{at}umn.edu

³ Abbreviations used in this paper: _c, common chain; BM, bone marrow; p, phosphorylated; SP, single-positive thymocyte; DP, double-positive thymocyte; GSK3β, glycogen synthase kinase-3 β; sµHC, surface µ H chain; PTEN, phosphatase and tensin homologue; SOCS-1, suppressor of cytokine signaling-1.