Lin, Jean
(2012)
Tim-1 signaling and localization during T cell activation.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
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.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| 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 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/16777 |
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