Treatment of mice with IGF-I stimulates T and B cell development. We showed that overexpression of IGF-II in transgenic FVB/N mice only stimulated T cell development. In the present study, we further addressed the in vivo effects of IGF-II in the absence of IGF-I to get more insight into the potential abilities of IGF-II to influence T and B cell development. To this end, we studied lymphocyte development in IGF-II transgenic Snell dwarf mice that are prolactin, GH and thyroid-stimulating hormone deficient and as a consequence show low serum IGF-I levels. We showed that T cell development was stimulated to the same extent as in IGF-II transgenic FVB/N mice. Furthermore, IGF-II increased the number of nucleated bone marrow cells and the number of immature B cells without having an effect on the number of mature B cells in spleen and bone marrow. Our data show that IGF-II has preferential effects on T cell development compared with B development, and that these preferential effects also occur in the absence of measurable IGF-I levels.

Insulin-like growth factor I (IGF-I) has been implicated to play a regulatory role in T cell development and in T cell function. We investigated the expression of type I IGF receptors on human peripheral T cells related to the maturation and activation stage using the type I IGF receptor-specific monoclonal antibody alpha IR3. It appeared that 87% of the CD4+CD45RA+ cells and 66% of the CD8+CD45RA+ cells were alpha IR3+, whereas only 37% of the CD4+CD45R0+ cells and 38% of the CD8+CD45R0+ cells bound alpha IR3. We also found that the fraction of alpha IR3+ cells within in vivo or in vitro activated (HLA-DR+) T cells is markedly lower than in nonactivated (HLA-DR-) cells. In vitro phytohemagglutinin-activated T cells and CD4+CD45R0+ cells activated with recall antigens also contained less alpha IR3+ cells (1-6%) than nonactivated cells (30-54%).

Insulin-like growth factor-I (IGF-I) has been implicated in playing a regulatory role in T cell development and in T cell function. We demonstrate the presence of type I IGF receptors on human thymocytes using radioligand binding assays and flowcytometric analysis. The relative potencies of IGF-I, IGF-II and insulin for competition with 125I- IGF-I indicate the presence of type I IGF receptors. Scatchard analysis revealed that the average number of receptors per thymocyte is 257 +/- 28 with a Kd of 0.12 +/- 0.01. With multicolour flowcytometry using a type I IGF receptor specific monoclonal antibody (alpha IR3), we show that CD4-CD8- cells express 3-4 times more receptors per cell as compared with CD4+CD8+, CD4+CD8- and CD4-CD8+ cells. IGF-I directly stimulated DNA synthesis of thymocytes and potentiated DNA synthesis in mitogen-activated thymocytes. These results indicate that IGF-I can influence T cell development in humans at the level of the thymus.

Growth hormone and insulin-like growth factor-I (IGF-I) have been demonstrated to play a role in T and B cell development. We studied the effects of IGF-II on T cell development in two transgenic mouse lines that overexpress human IGF-II under the control of the H2Kb promoter. The thymuses of 1-wk-old mice of two transgenic lines (5'-35 and 5'-74) contained 36 and 68%, respectively, more thymocytes than controls. Between 1 and 4 wk of age, the overexpression of IGF-II also resulted in a 2 to 2.5 times stronger increase in thymic cellularity. As in control mice, the number of thymocytes declined after 4 wk of age, and at 15 wk it was no longer significantly different from controls. Flowcytometric analysis indicated that at 2 and 4 wk of age, the increased thymic cellularity was associated with an increased number of early (CD4- CD8- or CD4- CD8dim), intermediate (CD4+CD8+), and mature thymocytes (CD3++CD4+CD8- or CD3++CD4-CD8+). However, the increase in the number of CD4+CD8- thymocytes was larger than the increase in the number of CD4-CD8+ thymocytes. As a consequence, CD4+ T cells mainly contributed to the increase in the number of T cells in spleen. These T cells showed a mature phenotype since they expressed CD3 and were negative for heat-stable antigen, a marker for immature T cells. These data indicate that overexpression of IGF-II increases thymic cellularity and stimulates the generation of phenotypically normal T cells with a preference to CD4+ cells.