Tim-1 signaling and localization during T cell activation

[摘要] Transmembrane immunoglobulin and mucin 1 (Tim-1) belongs to a family of cell surface proteins with roles in immune regulation, among other functions.Tim-1 polymorphisms have been implicated in human asthma susceptibility, and antibody modulation of Tim-1 has been shown to modulate murine models of autoimmune disease and allograft tolerance.This ability of Tim-1 to influence disease progression has been attributed to its role in co-stimulating T cell function, inducing transcriptional activation, and skewing cytokine production.Despite the emerging role of Tim-1 in immune modulation, the molecular mechanisms underlying Tim-1 function remain largely unidentified.We and others have demonstrated that Tim-1 is a co-stimulatory molecule with the ability to enhance transcriptional activation.However, it is unknown where Tim-1 localizes upon T cell activation, an avenue of investigation that has yielded important insights about other molecules involved in T cell activation.Using imaging, I demonstrate that in contrast to most co-stimulatory molecules, murine Tim-1 localizes away from the immunological synapse, and towards the distal pole complex in manner dependent on ezrin/radixin/moesin (ERM) family proteins.This localization is important for Tim-1 enhancement of cytokine production.In addition, a variety of molecular, pharmacological, and biochemical methods were used to examine the molecules and pathways induced downstream of Tim-1 activation.In particular, I discovered that Tim-1 can trigger NFAT/AP-1 activation in a PLC-1 independent, but TCR- and CD28-dependent, manner. Overall, this dissertation reveals some of the complexity underlying Tim-1 function.Better understanding of where and how Tim-1 interacts with other molecules will provide greater insight into Tim-1 mediated T cell activation and disease modulation.

[发布机构] the University of Pittsburgh