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Epidermal Growth Factor (EGF) Modulates Fetal Thymocyte Growth and Differentiation: Partial Reversal by Insulin, Mimicking by Specific Inhibitors of EGF Receptor Tyrosine Kinase Activity, and Differential Expression of CD45 Phosphatase Isotypes¹

Claudia S. Freitas^2,*, Sergio R. Dalmau^*, and Wilson Savino

^* Department of Immunology, Basic Research Center, National Cancer Institute of Rio de Janeiro, Rio de Janeiro, Brazil; Department of Biochemistry, Institute of Biology, Rio de Janeiro State University, Rio de Janeiro, Brazil; and Laboratory on Thymus Research, Institute Oswaldo Cruz, Foundation Oswaldo Cruz, Rio de Janeiro, Brazil

We have recently reported that epidermal growth factor (EGF) modulates thymocyte development in fetal thymus organ cultures. Exogenously added EGF arrested thymocyte growth and differentiation, acting at the transition from the CD4^-CD8^- (double-negative (DN)) to the CD4⁺CD8⁺ (double-positive (DP)) phenotype. In this study, we further investigate some molecular aspects of this blockade. This inhibitory effect could be mimicked by tyrphostins, which are selective inhibitors of EGF receptor kinase activity. An attempt to use insulin (INS) as a synergizing effector resulted in partial restoration of lobe cellularity, leading to expansion of the CD44^-CD25⁺ DN subset. However, INS did not overcome the EGF-driven blockade of the thymocyte DN DP transition. Analysis of CD45 phosphatase showed that this transition was preceded by a rise in CD45RB isotype expression. At the end of a 7-day culture, the remaining DN cells from both EGF- and EGF+INS-treated fetal thymus organ cultures showed a CD45RB^- phenotype and were negative for the EGF-immunoreactive molecule described previously on the fetal thymocyte surface. This finding implies that neither molecule is related to the growth capability of cells at this early developmental stage; it is more likely that the molecules are related to subsequent events in the thymocyte pathway to the DP phenotype. Thus, our data support the concept that EGF receptor-related circuitry may be relevant in thymus ontogeny. Additionally, evidence is provided for the duality between growth and differentiation at this particular early stage of thymocyte development.

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