ARF6 : a potential player in T-cell biology

Abstract

The ADP ribosylation factor (Arf) family of GTPases comprises of small (20-25kDa molecular mass) monomeric proteins. Among the 3 known subclasses, the highly expressed Arf6 (Class Ill) is functionally distinct, and is implicated ubiquitously in membrane trafficking, endocytosis, exocytosis in various cells and invasive activities of cancerous cells. There is very little known about the role of Arf6 towards the mechanisms of T cell signal transduction and Arf6 null embryos are lethal at midgestation which limits the role of KO models for investigating its regulatory mechanisms. We sought to study the role of Arf6 in T cell signalling. In the present piece of work, it was found that disruption of Arf6 activity leads to impairment of downstream signalling events underlying TCR signalling. This includes cell cycle progression, proliferation and expansion of T cells, IL -2 prod uction and ERK phosphorylation. These effects are mediated by cytohesins that function as regulating factors for Arf6. Moreover, it was found that Arf6 is specifically regulated in actively dividing immune cells like thymocytes, splenocytes, effector T cells. Also, regulatory T cells express high levels of Arf6 and secrete high levels of suppressive cytokine IL-10, indicating a potential role of Arf6 in inhibition of activation of T cells. Lastly, some of our pilot studies demonstrate that Arf6 has a role in the processes leading to in antigen presentation by Des. The data provides direct evidence that Arf6 constitutes an important 6omponent-of--TCR signalling- in primary Tlymphocytes and interaction between T cells and DCs. To study the mechanistic regulation of Arf6, in vivo models would prove to be an important asset. For this, I have developed a targeting vector to conditionally delete Arf6 in T cells, DCs or any other immune effector cells to elucidate the exact role of Arf6 in an in vivo setting. I anticipate that the conditional knockout model will allow a 'more precise and detailed analysis of Arf6 regulation in T cell as well as DCs and expand our understanding of human disease associated with immune dysregulation.EThOS - Electronic Theses Online ServiceGBUnited Kingdo