MicroRNA-29a attenuates CD8 T cell exhaustion and induces memory-like CD8 T cells during chronic infection.

Autor:	Stelekati E; Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33136.; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136., Cai Z; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., Manne S; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., Chen Z; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., Beltra JC; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., Buchness LA; Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33136.; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136., Leng X; Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33136.; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136., Ristin S; Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33136.; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136., Nzingha K; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., Ekshyyan V; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., Niavi C; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., Abdel-Hakeem MS; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., Ali MA; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., Drury S; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., Lau CW; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., Gao Z; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136.; Division of Surgical Oncology, Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136., Ban Y; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136.; Department of Public Health Sciences, Miller School of Medicine, University of Miami, Miami, FL 33136., Zhou SK; Sandler Asthma Basic Research Center, University of California, San Francisco, CA 94143.; Department of Microbiology & Immunology, University of California, San Francisco, CA 94143., Ansel KM; Sandler Asthma Basic Research Center, University of California, San Francisco, CA 94143.; Department of Microbiology & Immunology, University of California, San Francisco, CA 94143., Kurachi M; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., Jordan MS; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., Villarino AV; Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33136.; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136., Ngiow SF; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., Wherry EJ; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2022 Apr 26; Vol. 119 (17), pp. e2106083119. Date of Electronic Publication: 2022 Apr 21.
DOI:	10.1073/pnas.2106083119
Abstrakt:	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.
Databáze:	MEDLINE
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