期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 115, 期 10, 页码 2455-2460出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1712107115
关键词
T cell exhaustion; LCMV; chronic infection; co-stimulation; mTOR
资金
- National Institutes of Health [AI109605, CA206517]
- American Association of Immunologists Careers in Immunology Fellowship
- NIH [EY08098]
- NATIONAL CANCER INSTITUTE [R01CA206517] Funding Source: NIH RePORTER
- NATIONAL EYE INSTITUTE [P30EY008098] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R03AI109605] Funding Source: NIH RePORTER
Tim-3 is highly expressed on a subset of T cells during T cell exhaustion in settings of chronic viral infection and tumors. Using lymphocytic choriomeningitis virus (LCMV) Clone 13, a model for chronic infection, we found that Tim-3 was 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-lived effector T cells, at the expense of memory precursor development, after acute LCMV infection. These effects were accompanied by increased Akt/mTOR signaling in T cells expressing endogenous or ectopic Tim-3. Conversely, Akt/mTOR signaling was reduced in effector T cells from Tim-3-deficient mice. Thus, Tim-3 is essential for optimal effector T cell responses, and may also contribute to exhaustion by restricting the development of long-lived memory T cells. Taken together, our results suggest that Tim-3 is actually more similar to costimulatory receptors that are up-regulated after T cell activation than to a dominant inhibitory protein like PD-1. These findings have significant implications for the development of anti-Tim-3 antibodies as therapeutic agents.
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