Abnormal thymic microenvironment in insulin-like growth factor-II transgenic mice.
OBJECTIVE
Intrathymic T cell differentiation is driven by the thymic microenvironment, a tridimensional network of cells and extracellular matrix (ECM). Previous data showed that lymphoid and microenvironmental compartments are under the control of hormones and growth factors. We then attempted to define if insulin-like growth factor-II (IGF-II) was also involved in such a control.


METHODS
We used IGF-II transgenic (Tg) mice and studied their thymic microenvironment by immunohistochemistry. Moreover, we evaluated thymocytes in terms of their ability to adhere to thymic epithelial cells and to migrate through epithelial cells and ECM.


RESULTS
Transgenic IGF-II expression results in abnormalities of the thymic epithelium. Terminal differentiation of thymic epithelial cells (TEC) is modified, with the appearance of large clusters of cells immunoreactive to the monoclonal antibody KL1, which specifically recognizes highly differentiated TEC. Accordingly, treatment of cultured TEC with exogenous IGF-II induces the appearance of KL1+ cells and increases TEC proliferation. IGF-II Tg animals exhibit increased serum levels of the TEC-derived hormone thymulin. These effects were seen even when the IGF-II transgene was inserted in dwarf mice. Moreover, deposition of fibronectin and laminin is also enhanced in IGF-II Tg mouse thymus and in IGF-II-treated TEC cultures. Furthermore, ECM-mediated interactions between thymocytes and TEC are affected by exogenous IGF-II, as exemplified by the enhancement of thymocyte adhesion to TEC monolayers and thymocyte migration in thymic nurse cell complexes.


CONCLUSIONS
Our data indicate that IGF-II pleiotropically affects the thymic epithelium, both in vivo and in vitro, and that some of these changes may have consequences on thymocyte/TEC interactions.
Savino
Wilson
W
Laboratory on Thymus Research, Department of Immunology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil. savino@fiocruz.br
Cotta-de-Almeida
Vinícius
V
van Buul-Offers
Sylvia C
SC
Koster
Johanna G
JG
Dardenne
Mireille
M
D000818:Animals; D000911:Antibodies, Monoclonal; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D007150:Immunohistochemistry; D007335:Insulin-Like Growth Factor II / Q000235:genetics* / Q000494:pharmacology; D007797:Laminin / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D013935:Thymic Factor, Circulating / Q000378:metabolism; D013950:Thymus Gland / Q000002:abnormalities* / Q000166:cytology* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D000911:Antibodies, Monoclonal; D005353:Fibronectins; D007797:Laminin; D007335:Insulin-Like Growth Factor II; D013935:Thymic Factor, Circulating