The process of T-cell costimulation is a critical process in the immune response that influences T-cell proliferation, cytokine production and survival. Classically it involves the activation of cell surface molecules that alone are incapable of activating T-cells but rather amplify or repress molecular signals generated by the T-cell Receptor (TCR). In this study we provide evidence that IGF-/IGF-1 receptor (IGF-IR) axis represents a true costimulatory system in human T-cells. The IGF-1 system is a well characterized stimulator of cell growth, differentiation, and tumor progression and “cross-talks” with a wide range of other receptors. The interplay between the IGF-1 system and elements of T cell activation machinery is less understood. Our data show significant costimulating effects of IGF on proliferation of primary mouse and human T-cells. It increases IL-2 production, proliferation and viability of CD3+ cells in response to stimulating agents and costimulates cytotoxicity of CD8+ cells. We show that IGF-1 driven regulation is dependent on the differentiation state of the cell and has influence on both cytokine gene and immediate early gene expression. Major intracellular targets and pathways through which IGF-1 acts in synergy with TCR-derived signals involve Akt, ERK, NF-kappa B and CREB activation. Increased levels of IGF-I mRNA in CD3/CD28/IGF-1 stimulated PBMC cells provides evidence of an inducible autocrine regulation. We present evidence that the lymphoid oncogene TPL2 is an important target for IGF-1 in activated T-cells and transformed leukemia cells, suggesting a possible oncogenic linkage between elevated IGF-1 expression and lymphoid malignancies. Finally, we propose that TPL2 is a key regulator of a feedforward network motif in control of secondary effectors (JNK, MEK, Fos etc) that influence a common set of target genes. Since both regulators are positive this loop will provides a sustained signal to promote T-cell proliferation and cytokine production. In conclusion, our data demonstrate a close involvement of the IGF-I/IGF-IR axis in the complex processes of T-cell activation, proliferation and survival; thereby implicating a major role for IGF-1 in both T-cell homeostasis and tumor progression.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA