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Mechanisms of Tim-3 Signal Transduction in the Modulation of Downstream TCR Signaling

Lee, Judong (2013) Mechanisms of Tim-3 Signal Transduction in the Modulation of Downstream TCR Signaling. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Lee, Judongjul35@pitt.eduJUL35
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorKane, Lawrence Plkane@pitt.eduLKANE
Committee MemberGaffen, Sarah Lsig65@pitt.eduSIG65
Committee MemberJiang, Yuyuj5@pitt.eduYUJ5
Committee MemberLu, Binfengbinfeng@pitt.eduBINFENG
Committee MemberMorel, Penelope Amorel@pitt.eduMOREL
Committee MemberSarkar, Saumendra Nsaumen@pitt.eduSAUMEN
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

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  • Mechanisms of Tim-3 Signal Transduction in the Modulation of Downstream TCR Signaling. (deposited 01 Mar 2013 18:27) [Currently Displayed]


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