The use of growth factors to modulate the activities of antigen–specific CD8+ T cells in vitro

Rationale: Adoptive T cell therapy depends on the harvesting of the cells from the host, their activation in vitro, and their infusion back to the same host. The way of activating the T cells in vitro is a critical factor for their homing, survival and function in vivo. Sustaining T cell homing molecules, particularly CD62L, is benefic for the trafficking of the adoptive transferred cells. Objective: The aim of the present study is to test whether insulin–like growth factor–1 (IGF–1), thymosin– α1 (T–α1) as well as all–trans retinoid acid (ATRA) alone or in combination with IL–2, IL–12, IL–15 can enhance the activation and survival phenotypes of antigen-activated T cells in vitro. Methods & Results: To this end, OT–1 transgenic T cells were used as a model. These CD8+ T cells recognize OVA peptide presented by MHC class–I. The results showed that antigen stimulation of OT1 cells resulted in their activation as evidenced by the decrease in surface expression of CD62L, analyzed for 3 days after antigen stimulation and was more pronounced on day 5. The addition of IL–12 or IGF–1 alone but not of IL–2, IL–15 augmented OT–1 cell activation measured on day 5. Interestingly, the combination of IL–12 with IGF–1 sustained the expression of CD62L on OT1 cells. Although the addition of ATRA alone or in combination with IL–12 resulted in decreases in CD62L expression on day 3, they showed a dose–dependent effect on the restoration of CD62L expression on day 5. The analysis of the activation–induced cell death (apoptosis) of OT1 cells showed an increased rate of death on day 5 than on day 3–post antigen stimulation. The addition of only IL–12 or IGF–1 alone, but not of IL–2, IL–15 or T– α1, decreased OT1 cell apoptosis on day 3. These anti–apoptotic effects of IL–12 and IGF– 1, however, were recovered on day 5–post stimulation. Discussion: In conclusion, these results indicate that the activation phenotype and the survival of antigen–specific T cells can be differently modulated by immunomodulatory factors, where, interleukin–12 and IGF–1 induced the favorable effect. These results have a significant implication for T cell adoptive immunotherapy in different settings.