| dc.description.abstract | The multipotent naïve T cell of the immune system differentiates to mature, highly functional effector cells and differentiation is influenced by the microenvironment in which the T cell finds itself. Co-stimulatory molecules, local cytokines and other biological factors can tune the differentiation process and influence the differentiation outcomes. In this study, we investigated transcription factors and proteins activated downstream of co-stimulation through CD28 and ICAM-1. We observed that FAST-1, a DNA binding protein, activated only upon co- stimulation through ICAM-1. Co-stimulation through CD28 induced phosphorylation of receptor tyrosine kinases Csk, Dtk, FGFR1 and ROR2, while co-stimulation through ICAM-1 induced phosphorylation of Hgfr, IGF-1R, MuSK and EpHA8. Hence, specific sets of proteins were activated downstream of each co-stimulatory molecule leading to activation of unique signaling pathways. We also investigated the early signaling process upon engagement of CD45 alone or in association with CD28. CD45 plays a crucial role in initiating T cell signaling by dephosphorylating a negative regulatory tyrosine residue in Src family kinases such as Lck. We observed that engagement of CD45 alone induced signaling in T cells. We also observed that TCR/CD3 stimulation with CD45 promoted prolonged Lck association with the TCR/CD3 complex and Lck remained associated during TCR/CD3+CD28+CD45 stimulation. We concluded that Lck association is dependent on TCR/CD3 and CD45 engagement. Next, we examined the effect of statins on T cell function. We observed that upon CD28 co-stimulation, pravastatin induced increased T cell activation, proliferation and differentiation to effector and memory phenotypes, while upon ICAM-1 co-stimulation, pravastatin induced decreased T cell activation, proliferation and differentiation to effector and memory phenotypes. Pravastatin treatment promoted increased differentiation to the Treg subset upon co-stimulation through both CD28 and ICAM-1. Hence, we concluded that the choice of co-stimulatory molecule influenced T cell function. Finally, we investigated the influence of low pH on chemokine receptor expression on leukemic T cell lines (Jurkat and Molt-3) and primary T cells. Low pH treatment had no effect on chemokine receptor expression in primary T cells. Transient low pH resulted in an increase in CCR5 expression in Molt-3 but a decrease in Jurkat cells. In both Jurkat and Molt-3, transient low pH had a dramatic effect on CXCR4 expression and decreased CCR7 expression. In conclusion, low pH microenvironment influenced the expression of chemokine receptors differently in leukemic T cell lines and primary T cells. | |
