eprintid: 34548
rev_number: 53
userid: 7409
dir: disk0/00/03/45/48
datestamp: 2018-09-17 20:39:06
lastmod: 2018-09-17 20:39:06
status_changed: 2018-09-17 20:39:06
type: thesis_degree
metadata_visibility: show
contact_email: lyndsay.ave@gmail.com
eprint_status: archive
creators_name: Avery, Lyndsay
creators_email: lya2@pitt.edu
creators_id: lya2
creators_orcid: 0000-0002-8148-1648
title: Tim-3 co-stimulation promotes short-lived effector T cells, restricts memory precursors, and is dispensable for T cell exhaustion
ispublished: unpub
divisions: sch_gsph_infectiousdiseasesmicrobiology
full_text_status: public
keywords: T cell exhaustion
LCMV
chronic infection
mTOR
T cells
Tim-3
immunotherapy
abstract: Tim-3 is highly expressed on a subset of T cells during T cell exhaustion, in settings of chronic viral infection and in tumors. Using LCMV Clone 13, a model for chronic infection, we have found that Tim-3 is neither necessary nor sufficient for the development of T cell exhaustion. Nonetheless, expression of Tim-3 was sufficient to drive resistance to PD-L1 blockade therapy during chronic infection. Strikingly, expression of Tim-3 promoted the development of short-term effector T cells, at the expense of memory precursor development, following acute infection with LCMV-Armstrong. These effects were accompanied by increased Akt/mTOR signaling in T cells with endogenous or ectopically expressed Tim-3. Conversely, Akt/mTOR signaling was reduced in effector T cells from Tim-3 deficient mice. Thus, Tim-3, while essential for optimal effector T cell responses, but may also contribute to T cell exhaustion is restricting the development of long-lived memory T cells. Taken together, our results suggest that Tim-3 is more similar to co-stimulatory receptors that are upregulated following T cell activation, rather than dominant inhibitory proteins such as PD-1. These findings have significant implications for the development of anti-Tim-3 antibodies as immunotherapy agents for the treatment of cancer, infections, and other matters of public health.
date: 2018-09-17
date_type: published
pages: 133
institution: University of Pittsburgh
refereed: TRUE
etdcommittee_type: committee_chair
etdcommittee_type: committee_cochair
etdcommittee_type: committee_member
etdcommittee_type: committee_member
etdcommittee_type: committee_member
etdcommittee_name: Kane, Lawrence
etdcommittee_name: Rinaldo, Charles
etdcommittee_name: Mailliard, Robbie
etdcommittee_name: Lu, Binfeng
etdcommittee_name: Hendricks, Robert
etdcommittee_email: lkane@pitt.edu
etdcommittee_email: rinaldo@pitt.edu
etdcommittee_email: rbm19@pitt.edu
etdcommittee_email: binfeng@pitt.edu
etdcommittee_email: hendricksrr@upmc.edu
etdcommittee_id: lkane
etdcommittee_id: rinaldo
etdcommittee_id: rbm19
etdcommittee_id: binfeng
etdcommittee_id: rlh13
etdcommittee_orcid: 0000-0001-5198-516X
etdcommittee_orcid: 0000-0001-5501-503X
etdcommittee_orcid: 0000-0001-7419-2912
etd_defense_date: 2018-04-25
etd_approval_date: 2018-09-17
etd_submission_date: 2018-05-24
etd_release_date: 2018-09-17
etd_access_restriction: immediate
etd_patent_pending: FALSE
thesis_type: dissertation
degree: PhD
citation:   Avery, Lyndsay  (2018) Tim-3 co-stimulation promotes short-lived effector T cells, restricts memory precursors, and is dispensable for T cell exhaustion.  Doctoral Dissertation, University of Pittsburgh.    (Unpublished)  
document_url: http://d-scholarship-dev.library.pitt.edu/34548/1/AveryL_ETD_June2018.pdf