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miR-150 Regulates Differentiation and Cytolytic Effector Function in CD8+ T cells
Norah L Smith1, Erin M Wissink2, Andrew Grimson2
1Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853.
Abstract:
MicroRNAs regulate most mammalian genes, and they control numerous aspects of immune system development and function. Their precise roles in the CD8+ T cell response, however, remain unclear. In this report, we show that in the absence of the microRNA miR-150, CD8+ T cells fail to undergo robust expansion and differentiation into short-lived terminal effector cells in response to primary infection with Listeria monocytogenes or Vaccinia virus. Notably, even after transitioning into the memory pool, miR-150(-/-) cells still mount a weaker recall response to secondary infection, and remain less differentiated than their wild-type counterparts. Transcriptome analysis shows miR-150 gene targets are globally upregulated in cells lacking miR-150, and amongst these targets, we found misregulation of genes associated with proliferation and effector cell function. These transcriptome data suggest that miR-150 deficient CD8+ T cells are less efficient in killing infected cells, which we validate experimentally. Together, these results reveal a cell-intrinsic role for miR-150 in the regulation of effector CD8+ T cell fate and function.
Insights
MicroRNA 150 (miR-150) is crucial for CD8+ T cell expansion and effector function during infection. Its absence impairs both primary and memory responses, highlighting its cell-intrinsic role in T cell immunity.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- MicroRNAs (miRNAs) are key regulators of gene expression impacting immune cell development and function.
- The specific role of miRNAs, particularly miR-150, in CD8+ T cell responses remains largely undefined.
Purpose of the Study:
- To elucidate the function of miR-150 in CD8+ T cell responses to infection.
- To investigate the impact of miR-150 deficiency on T cell expansion, differentiation, and effector functions.
Main Methods:
- Utilized mouse models deficient in miR-150 (miR-150(-/-)).
- Infected mice with Listeria monocytogenes and Vaccinia virus to assess primary immune responses.
- Analyzed CD8+ T cell expansion, differentiation, and memory formation.
- Performed transcriptome analysis to identify miR-150 gene targets.
- Experimentally validated the impact on cytotoxic T cell function.
Main Results:
- Absence of miR-150 led to impaired CD8+ T cell expansion and differentiation into effector cells post-infection.
- miR-150(-/-) CD8+ T cells exhibited a weaker recall response and reduced differentiation in the memory pool.
- Transcriptome analysis revealed global upregulation of miR-150 targets, including genes involved in proliferation and effector functions.
- miR-150 deficient CD8+ T cells demonstrated reduced efficiency in killing infected target cells.
Conclusions:
- miR-150 plays a critical cell-intrinsic role in regulating CD8+ T cell fate, proliferation, and effector functions.
- This microRNA is essential for robust CD8+ T cell responses during both primary and secondary infections.
- Understanding miR-150's function provides insights into adaptive immunity and potential therapeutic targets.
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