Lee, Judong
(2013)
Mechanisms of Tim-3 Signal Transduction in the Modulation of Downstream TCR Signaling.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
This is the latest version of this item.
Abstract
T-cell immunoglobulin and mucin 3 protein (Tim-3) is a type-I transmembrane protein known to negatively regulate Th1 and Th17 CD4 T cells, and CD8 T cell mediated immune responses. Tim-3 expression level correlates with the severity of T cell exhaustion under conditions of chronic viral infection and tumor burden and Tim-3 antibodies can reverse this dysfunctional phenotype. Exploring the signal transduction mechanism of Tim-3, I demonstrated that ectopic expression of Tim-3 enhanced NFAT/AP-1, NFAT and NF-κB reporter activity induced by TCR stimulation, and enhanced AP-1 reporter activity independent of TCR stimulation. Two tyrosines in the cytosolic tail of Tim-3 are responsible for the potentiation of signal transduction by TCR in a redundant manner. I demonstrated that the Src family kinase (SFK) Fyn can phosphorylate Y256 and Y263 residues of Tim-3. An SH2 domain screen and co-immunoprecipitation identified p85 PI3K interaction with Tim-3 in a tyrosine phosphorylation-dependent manner. I also found that Tim-3 expression upregulates phosphorylation of PLC-γ1 and MAP kinases ERK1/2, p38, and JNK. Finally, I demonstrated that Tim-3 upregulates phosphorylation of ribosomal protein S6, a downstream target of PI3K and ERK, and IL-2 secretion induced by TCR stimulation. I conclude that potentiation of NFAT/AP1 and NF-κB activity by Tim-3 is mediated by enhancement of the PI3K, PLC-γ1 and ERK pathways. Thus, we have demonstrated a paradoxical activating function of Tim-3 in TCR signaling, while Tim-3 is known as a negative regulator of Th1 and Tc1 T cell mediated immune responses. This augmentation of TCR signaling by Tim-3 may contribute to driving and/or maintaining T cell exhaustion. Alternatively, Tim-3 may have a dual activation and inhibition role depending on the ligands available at a particular stage of T cell activation.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
1 March 2013 |
| Date Type: |
Publication |
| Defense Date: |
8 January 2013 |
| Approval Date: |
1 March 2013 |
| Submission Date: |
21 February 2013 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
137 |
| 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-3, T cell activation, T cell signaling, phosphorylation |
| Date Deposited: |
01 Mar 2013 18:27 |
| Last Modified: |
15 Nov 2016 14:09 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/17425 |
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Mechanisms of Tim-3 Signal Transduction in the Modulation of Downstream TCR Signaling. (deposited 01 Mar 2013 18:27)
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