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Tim-3 co-stimulation promotes short-lived effector T cells, restricts memory precursors, and is dispensable for T cell exhaustion

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 (Unpublished)

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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.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Avery, Lyndsaylya2@pitt.edulya20000-0002-8148-1648
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairKane, Lawrencelkane@pitt.edulkane0000-0001-5198-516X
Committee CoChairRinaldo, Charlesrinaldo@pitt.edurinaldo
Committee MemberMailliard, Robbierbm19@pitt.edurbm190000-0001-5501-503X
Committee MemberLu, Binfengbinfeng@pitt.edubinfeng
Committee MemberHendricks, Roberthendricksrr@upmc.edurlh130000-0001-7419-2912
Date: 17 September 2018
Date Type: Publication
Defense Date: 25 April 2018
Approval Date: 17 September 2018
Submission Date: 24 May 2018
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 133
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Infectious Diseases and Microbiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: T cell exhaustion LCMV chronic infection mTOR T cells Tim-3 immunotherapy
Date Deposited: 17 Sep 2018 20:39
Last Modified: 17 Sep 2018 20:39
URI: http://d-scholarship.pitt.edu/id/eprint/34548

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