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LAG-3 Confers a Competitive Disadvantage upon Antiviral CD8+ T Cell Responses
Kevin D Cook1, Jason K Whitmire2
1Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, NC 27599; and.
Abstract:
Ongoing clinical trials are evaluating the benefits of systemic blockade of lymphocyte activation gene-3 (LAG-3) signals to improve immunity to tumors. Those studies are founded on the well-established inhibitory role of LAG-3 in regulating CD8(+) T cells during chronic virus infection and antitumor responses. However, the T cell response in LAG-3-deficient mice is similar in size and function to that in wild type animals, suggesting LAG-3 has nuanced immune-regulatory functions. We performed a series of adoptive transfer experiments in mice to better understand the T cell-intrinsic functions of LAG-3 in the regulation of CD8(+) T cell responses. Our results indicate that LAG-3 expression by CD8(+) T cells inhibits their competitive fitness and results in a slightly reduced rate of cell division in comparison with LAG-3-deficient cells. This cell-intrinsic effect of LAG-3 was consistent across both acute and chronic virus infections. These data show that LAG-3 directly modulates the size of the T cell response and support the use of LAG-3 blockade regimens to enhance CD8(+) T cell responses.
Insights
Blockading lymphocyte activation gene-3 (LAG-3) signals may enhance anti-tumor immunity. New research shows LAG-3 expression on CD8(+) T cells intrinsically limits their proliferation, suggesting LAG-3 blockade can boost T cell responses.
Area of Science:
- Immunology
- Molecular Biology
- Cancer Research
Background:
- Lymphocyte activation gene-3 (LAG-3) is known to inhibit T cell responses.
- LAG-3 blockade is being investigated in clinical trials to enhance anti-tumor immunity.
- Previous studies suggested nuanced roles for LAG-3, as LAG-3-deficient mice showed similar T cell responses to wild-type animals.
Purpose of the Study:
- To investigate the T cell-intrinsic functions of LAG-3 in regulating CD8(+) T cell responses.
- To elucidate the specific mechanisms by which LAG-3 influences T cell proliferation and fitness.
Main Methods:
- Adoptive transfer experiments in mouse models.
- Comparison of T cell responses in LAG-3-deficient and wild-type mice during viral infections.
Main Results:
- LAG-3 expression on CD8(+) T cells intrinsically inhibits their competitive fitness.
- LAG-3-expressing CD8(+) T cells exhibited a reduced rate of cell division compared to LAG-3-deficient cells.
- This cell-intrinsic inhibitory effect of LAG-3 was observed in both acute and chronic viral infections.
Conclusions:
- LAG-3 directly modulates the size of the CD8(+) T cell response.
- Targeting LAG-3 through blockade regimens holds promise for enhancing CD8(+) T cell-mediated immunity against tumors and infections.
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