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Tim-3: Regulation of T Cell Functions and Mechanism of Expression

Manandhar, Priyanka (2024) Tim-3: Regulation of T Cell Functions and Mechanism of Expression. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Tim-3 is a transmembrane protein that is commonly used as a marker for terminally exhausted CD8+ T cells in the contexts of chronic infections and tumors. However, Tim-3 is widely expressed on Th1 CD4+ T cells, regulatory T cells, dendritic cells and mast cells, in addition to activated CD8+ T cells. While Tim-3 has been shown to induce death in Th1 cells, it is co- stimulatory in T cells during acute stimulation and has been shown to activate the PI3K pathway. The germline deletion of Tim-3 in mice was previously shown to skew the CD8+ T cell response towards a memory phenotype in the context of LCMV Armstrong infection but the effects of Tim- 3 on CD8+ T cells at the effector stage of the infection remain unknown. In addition, it is not known whether different transcription factors regulate the expression of Tim-3 in conditions of acute vs. chronic stimulation. The transcription factor Blimp-1 has also been shown to co-express with Tim- 3 in acute and chronic infections. Although there are no predicted Blimp-1 binding sites in the Havcr2 locus, there are binding sites for E2A, leading us to predict that a Blimp-1-Id3-E2A transcription factor circuit may play a role in Tim-3 expression.
Using TIRF imaging, I have shown here that Tim-3 localizes to the immunological synapse during T cell activation. Using a novel Tim-3 truncation mutant and a CD8-specific knockout mouse model, I have also shown that Tim-3 is required for a robust CD8+ effector T cell response to LCMV Armstrong and Tim-3 expressing effector CD8+ T cells have an enhanced effector-like phenotype. Additionally, Blimp-1 and Id3 conditional knockout mice in chronic and acute infections show that Blimp-1 and Id3 regulate the expression of Tim-3 in CD8+ T cells.

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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Manandhar, Priyankaprm66@pitt.eduprm660000-0003-2868-5286
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairMorel, Penelopemorel@pitt.edumorel0000-0002-1743-3676
Committee MemberD'Cruz, Louiseldcruz@pitt.eduldcruz0000-0003-0388-430X
Committee MemberHand, Timothyhandt@pitt.eduhandt0000-0002-2684-9462
Committee MemberWilliams, Johnjvw@pitt.edujvw0000-0001-8377-5175
Thesis AdvisorKane, Lawrencelkane@pitt.edulkane0000-0001-5198-516X
Date: 14 October 2024
Date Type: Publication
Defense Date: 12 April 2024
Approval Date: 14 October 2024
Submission Date: 1 May 2024
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 157
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Immunology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: CD4 and CD8 T cells, T cell activation, T cell response to LCMV
Date Deposited: 14 Oct 2024 14:22
Last Modified: 14 Oct 2024 14:22
URI: http://d-scholarship.pitt.edu/id/eprint/46378

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