A molecular threshold for effector CD8(+) T cell differentiation controlled by transcription factors Blimp-1 and T-bet

Annie Xin; Frederick Masson; Yang Liao; Simon Preston; Tianxia Guan; Renee Gloury; Moshe Olshansky; Jian-Xin Lin; Peng Li; Terence P Speed; Gordon K Smyth; Matthias Ernst; Warren J Leonard; Marc Pellegrini; Susan M Kaech; Stephen L Nutt; Wei Shi; Gabrielle T Belz; Axel Kallies

doi:10.1038/ni.3410

A molecular threshold for effector CD8(+) T cell differentiation controlled by transcription factors Blimp-1 and T-bet

Nat Immunol. 2016 Apr;17(4):422-32. doi: 10.1038/ni.3410. Epub 2016 Mar 7.

Authors

Annie Xin^{1

2}, Frederick Masson^{1

2}, Yang Liao^{1

2}, Simon Preston^{1

2}, Tianxia Guan³, Renee Gloury^{1

2}, Moshe Olshansky^{1

4}, Jian-Xin Lin⁵, Peng Li⁵, Terence P Speed^{1

6}, Gordon K Smyth^{1

6}, Matthias Ernst^{1

2}, Warren J Leonard⁵, Marc Pellegrini^{1

2}, Susan M Kaech^{4

7}, Stephen L Nutt^{1

2}, Wei Shi^{1

6}, Gabrielle T Belz^{1

2}, Axel Kallies^{1

2}

Affiliations

¹ The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
² The Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
³ Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.
⁴ The Department of Computing and Information Systems, University of Melbourne, Parkville, Victoria, Australia.
⁵ Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
⁶ The Department of Mathematics and Statistics, University of Melbourne, Parkville, Victoria, Australia.
⁷ Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

PMID: 26950239
PMCID: PMC5779087
DOI: 10.1038/ni.3410

Abstract

T cell responses are guided by cytokines that induce transcriptional regulators, which ultimately control differentiation of effector and memory T cells. However, it is unknown how the activities of these molecular regulators are coordinated and integrated during the differentiation process. Using genetic approaches and transcriptional profiling of antigen-specific CD8(+) T cells, we reveal a common program of effector differentiation that is regulated by IL-2 and IL-12 signaling and the combined activities of the transcriptional regulators Blimp-1 and T-bet. The loss of both T-bet and Blimp-1 leads to abrogated cytotoxic function and ectopic IL-17 production in CD8(+) T cells. Overall, our data reveal two major overlapping pathways of effector differentiation governed by the availability of Blimp-1 and T-bet and suggest a model for cytokine-induced transcriptional changes that combine, quantitatively and qualitatively, to promote robust effector CD8(+) T cell differentiation.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Arenaviridae Infections / immunology
CD8-Positive T-Lymphocytes / immunology*
Cell Differentiation / immunology*
Chromatin Immunoprecipitation
Cytokines / immunology
Flow Cytometry
Gene Expression Profiling
Influenza A Virus, H1N1 Subtype
Interleukin-12 / immunology*
Interleukin-17 / immunology
Interleukin-2 / immunology*
Lymphocytic choriomeningitis virus
Mice
Orthomyxoviridae Infections / immunology
Positive Regulatory Domain I-Binding Factor 1
Real-Time Polymerase Chain Reaction
STAT4 Transcription Factor / immunology
STAT5 Transcription Factor / immunology
Sequence Analysis, RNA
Signal Transduction
T-Box Domain Proteins / immunology*
Transcription Factors / immunology*

Substances

Cytokines
Interleukin-17
Interleukin-2
Prdm1 protein, mouse
STAT4 Transcription Factor
STAT5 Transcription Factor
Stat4 protein, mouse
T-Box Domain Proteins
T-box transcription factor TBX21
Transcription Factors
Interleukin-12
Positive Regulatory Domain I-Binding Factor 1

Abstract

Publication types

MeSH terms

Substances

Grants and funding