Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form

Tim-1 signaling and localization during T cell activation

Lin, Jean (2012) Tim-1 signaling and localization during T cell activation. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

Primary Text

Download (3MB) | Preview


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.


Social Networking:
Share |


Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Lin, Jeanjyl8@pitt.eduJYL8
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairKane, Lawrencelkane@pitt.eduLKANE
Committee MemberLu, Binfengbinfeng@pitt.eduBINFENG
Committee MemberGaffen, Sarah Lsig65@pitt.eduSIG65
Committee MemberRay, Anuradharaya@pitt.eduRAYA
Committee MemberSmithgall, Thomas Etsmithga@pitt.eduTSMITHGA
Date: 14 December 2012
Date Type: Publication
Defense Date: 29 October 2012
Approval Date: 14 December 2012
Submission Date: 5 December 2012
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 167
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Immunology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Tim-1, T cell activation, distal pole complex, PLCg1, signaling
Date Deposited: 14 Dec 2012 15:25
Last Modified: 14 Dec 2017 06:15


Monthly Views for the past 3 years

Plum Analytics

Actions (login required)

View Item View Item