IL-7 activates the phosphatidylinositol 3-kinase/AKT pathway in normal human thymocytes but not normal human B cell precursors.
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-7Ralpha 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 beta, 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 beta. 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 Masonic Cancer Center and Department of Laboratory Medicine/Pathology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
Sonja E
SE
Johnson
Nisha
N
Shah
Anna A
AA
Bajer
Tucker W
TW
LeBien
D000328:Adult; D000818:Animals; D016175:B-Lymphocyte Subsets / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000276:immunology; D049109:Cell Proliferation; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000201:enzymology / Q000276:immunology; D004789:Enzyme Activation / Q000276:immunology; D004790:Enzyme Induction / Q000276:immunology; D006801:Humans; D015851:Interleukin-7 / Q000502:physiology*; D053699:Interleukin-7 Receptor alpha Subunit / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism* / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D013234:Stem Cells / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000201:enzymology* / Q000276:immunology
D015851:Interleukin-7; D053699:Interleukin-7 Receptor alpha Subunit; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; C508605:IL7 protein, human