High levels of IL-7 cause dysregulation of thymocyte development.
IL-7 signaling is required for thymocyte development and its loss has a severe deleterious effect on thymus function. Thymocyte-stromal cell interactions and other mechanisms tightly regulate IL-7 expression. We show that disruption of that regulation by over-expression of IL-7 inhibits T-cell development and promotes extensive B-cell lymphopoiesis in the thymus. Our data reveal that high levels of IL-7 negate Notch-1 function in thymocytes found in IL-7 transgenic mice and in co-culture with OP9-DL1 cells. While high levels of IL-7R are present on thymocytes, increased suppressor of cytokine signaling-1 expression blunts IL-7 downstream signaling, resulting in hypo-phosphorylation of proteins in the PI3K-Akt pathway. Consequently, GSK3β remains active and inhibits Notch-1 signaling as observed by decreased Hes-1 and Deltex expression in thymic progenitors. This is the first demonstration that high levels of IL-7 antagonize Notch-1 signaling and suggest that IL-7 may affect T- versus B-lineage choice in the thymus.
Experimental Immunology and Transplantation Branch, National Cancer Institute, Bethesda, MD 20892, USA. nahed.elkassar@ahrq.hhs.gov
Nahed
N
El-Kassar
Francis A
FA
Flomerfelt
Baishakhi
B
Choudhury
Lee A
LA
Hugar
Kevin S
KS
Chua
Veena
V
Kapoor
Philip J
PJ
Lucas
Ronald E
RE
Gress
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology*; D002454:Cell Differentiation; D018920:Coculture Techniques; D015851:Interleukin-7 / Q000235:genetics / Q000276:immunology*; D038041:Lymphopoiesis; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction; D017154:Stromal Cells / Q000166:cytology / Q000276:immunology; D050826:Suppressor of Cytokine Signaling Proteins / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology*; D060168:Thymocytes / Q000166:cytology*; D013950:Thymus Gland / Q000166:cytology / Q000254:growth & development / Q000276:immunology / Q000378:metabolism
D015851:Interleukin-7; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D050826:Suppressor of Cytokine Signaling Proteins