Exogenous insulin-like growth factor 1 enhances thymopoiesis predominantly through thymic epithelial cell expansion.
Insulin-like growth factor 1 (IGF-1) enhances thymopoiesis but given the broad distribution of IGF-1 receptors (IGF-1Rs), its mechanism of action has remained unclear. To identify points of thymic regulation by IGF-1, we examined its effects on T-cell precursors, thymocytes, and thymic epithelial cells (TECs) in normal and genetically altered mice. In thymus-intact but not thymectomized mice, IGF-1 administration increased peripheral naive and recent thymic emigrant (RTE) populations, demonstrating its effect on T-cell production, not peripheral expansion. IGF-1 administration increased bone marrow LSK (lineage(-), Sca-1(+), c-kit(+)) precursor proliferation and peripheral LSK populations, increased thymocyte populations in a sequential wave of expansion, and proportionately expanded TEC subpopulations and enhanced their chemokine expression. To separate IGF-1's effects on thymocytes and TECs, we generated mice lacking IGF-1R on thymocytes and T cells. Thymocyte and RTE numbers were decreased in these mice, but IGF-1 treatment produced comparable thymocyte numbers to similarly treated wild-type mice. We additionally separated thymic- from LSK-specific effects by demonstrating that IGF-1 increased thymocyte numbers despite impaired early thymic progenitor (ETP) importation in PSGL-1KO mice. These results indicate the critical point thymic function regulation by IGF-1 involves TEC expansion regulating thymocyte precursor entry and facilitating thymocyte development.
Chu
Yu-Waye
YW
Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Institutes of Health (NIH), Bethesda, MD, USA. chuy@mail.nih.gov
Schmitz
Sabrina
S
Choudhury
Baishakhi
B
Telford
William
W
Kapoor
Veena
V
Garfield
Susan
S
Howe
David
D
Gress
Ronald E
RE
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D002452:Cell Count; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D019070:Cell Lineage / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018925:Chemokines / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects; D013950:Thymus Gland / Q000166:cytology* / Q000187:drug effects*
D018925:Chemokines; D008562:Membrane Glycoproteins; C084882:P-selectin ligand protein; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1