Interferon regulatory factor 4 sustains CD8(+) T cell expansion and effector differentiation.

Abstract

Upon infection, CD8(+) T cells undergo a stepwise process of early activation, expansion, and differentiation into effector cells. How these phases are transcriptionally regulated is incompletely defined. Here, we report that interferon regulatory factor 4 (IRF4), dispensable for early CD8(+) T cell activation, was vital for sustaining the expansion and effector differentiation of CD8(+) T cells. Mechanistically, IRF4 promoted the expression and function of Blimp1 and T-bet, two transcription factors required for CD8(+) T cell effector differentiation, and simultaneously repressed genes that mediate cell cycle arrest and apoptosis. Selective ablation of Irf4 in peripheral CD8(+) T cells impaired antiviral CD8(+) T cell responses, viral clearance, and CD8(+) T cell-mediated host recovery from influenza infection. IRF4 expression was regulated by T cell receptor (TCR) signaling strength via mammalian target of rapamycin (mTOR). Our data reveal that IRF4 translates differential strength of TCR signaling into different quantitative and qualitative CD8(+) T cell responses.

• Authors: Shuyu Yao, Bruno Fernando Buzo, Duy Pham, Li Jiang, Elizabeth J Taparowsky, Mark H Kaplan, Jie Sun
• Journal: Immunity (Immunity) Vol. 39 Issue 5 Pg. 833-45 (Nov 14 2013) ISSN: 1097-4180 [Electronic] United States
• PMID: 24211184 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Apoptosis Regulatory Proteins
• Bcl-2-Like Protein 11
• Bcl2l11 protein, mouse
• Cyclin-Dependent Kinase Inhibitor Proteins
• Interferon Regulatory Factors
• Membrane Proteins
• Prdm1 protein, mouse
• Proto-Oncogene Proteins
• Receptors, Antigen, T-Cell
• T-Box Domain Proteins
• T-box transcription factor TBX21
• Transcription Factors
• interferon regulatory factor-4
• Positive Regulatory Domain I-Binding Factor 1
• mTOR protein, mouse
• TOR Serine-Threonine Kinases

Topics

• Animals
• Apoptosis
• Apoptosis Regulatory Proteins (antagonists & inhibitors)
• Bcl-2-Like Protein 11
• CD8-Positive T-Lymphocytes (cytology)
• Cell Differentiation
• Cells, Cultured (cytology)
• Coculture Techniques
• Cyclin-Dependent Kinase Inhibitor Proteins (antagonists & inhibitors)
• Dendritic Cells (immunology)
• Gene Expression Regulation
• Interferon Regulatory Factors (deficiency, genetics, immunology, physiology)
• Lymphocyte Activation
• Membrane Proteins (antagonists & inhibitors)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Orthomyxoviridae Infections (immunology, virology)
• Positive Regulatory Domain I-Binding Factor 1
• Proto-Oncogene Proteins (antagonists & inhibitors)
• Receptors, Antigen, T-Cell (immunology)
• Specific Pathogen-Free Organisms
• T-Box Domain Proteins (biosynthesis, genetics)
• TOR Serine-Threonine Kinases (physiology)
• Transcription Factors (biosynthesis, genetics)
• Viral Plaque Assay