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(Unpublished)
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
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| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| 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: |
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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