Intercellular Adhesion Molecule-1 Guides Naive T Cell Differentiation and Regulatory T Cell Induction

Abstract

The outcome of naïve T cell activation and differentiation is guided by cues received from the cellular microenvironment, including cytokine and costimulatory signals. Naïve T cell precursors can differentiate into a variety of cellular subsets, each with a unique function in the immune response. In this Dissertation, we provide supporting evidence for the participation of costimulatory molecules in cell fate decisions. Using an in vitro differentiation system, we demonstrate that costimulation through Intercellular Adhesion Molecule-1 (ICAM-1) on the naïve CD4+ T cell can promote differentiation to Foxp3hiCD25+CD127lo regulatory T (Treg) cells with suppressor function. These results add to the evidence previously published by our lab that ICAM-1 can act as a costimulatory molecule in the process of activation and differentiation of naïve CD4+ T cells from younger individuals. However, when naïve CD4+ T cells from older individuals were costimulated through ICAM-1, differentiation to effector and memory subsets was promoted, while differentiation to a Treg subset was impaired. These data contribute to the concept that aging may alter naïve T cell activation and differentiation. Next, we examined the in vivo role of ICAM-1 using mice deficient in ICAM-1 or doubly deficient in ICAM-1 and CD28. ICAM-1-/- mice tended to have slightly increased CD8+ T cell function compared to wild-type controls, while ICAM-1-/-CD28-/- mice displayed decreased CD8+ T cell function during acute viral infection. However, a lack of both ICAM-1 and CD28 did not completely abolish CD8+ T cell IFN-gamma production or cytotoxicity. Finally, we further compared costimulation of human naïve CD4+ T cells through ICAM-1 and CD28 and identified potential differences in the timing of activation, in cytokine secretion, and in kinase signaling. Together, our results suggest that costimulation through ICAM-1 can participate in the differentiation of Treg cells from naïve precursors, and that differences in the costimulatory signal can influence differentiation outcome.