期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2106083119
关键词
CD8 T cells; microRNA; exhaustion
资金
- NIH [5-R21-AI-144732-02, AI105343, AI112521, AI082630, AI201085, AI117950, HL109102, HL107202]
- National Cancer Institute of the National Institutes of Health [P30CA240139]
- Parker Institute for Cancer Immunotherapy
- cancer immunology program at the University of Pennsylvania
This study identifies miR-29a as a key regulator of exhausted CD8 T cells (TEX) during chronic viral infection. It shows that miR-29a improves CD8 T cell responses, inhibits exhaustion-driving transcriptional pathways, and regulates ribosomal biogenesis. As a result, miR-29a promotes a memory-like CD8 T cell differentiation state during chronic infection.
CD8 T cells mediate protection against intracellular pathogens and tumors. However, persistent antigen during chronic infections or cancer leads to T cell exhaustion, suboptimal functionality, and reduced protective capacity. Despite considerable work interrogating the transcriptional regulation of exhausted CD8 T cells (TEX), the posttranscriptional control of TEX remains poorly understood. Here, we interrogated the role of microRNAs (miRs) in CD8 T cells responding to acutely resolved or chronic viral infection and identified miR-29a as a key regulator of TEX. Enforced expression of miR-29a improved CD8 T cell responses during chronic viral infection and antagonized exhaustion. miR-29a inhibited exhaustion-driving transcriptional pathways, including inflammatory and T cell receptor signaling, and regulated ribosomal biogenesis. As a result, miR-29a fostered a memory-like CD8 T cell differentiation state during chronic infection. Thus, we identify miR-29a as a key regulator of TEX and define mechanisms by which miR-29a can divert exhaustion toward a more beneficial memory-like CD8 T cell differentiation state.
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