The transcription factor T-bet is induced by IL-15 and thymic agonist selection and controls CD8αα(+) intraepithelial lymphocyte development

Christoph S N Klose; Katharina Blatz; Yannick d'Hargues; Pedro P Hernandez; Michael Kofoed-Nielsen; Juliane F Ripka; Karolina Ebert; Sebastian J Arnold; Andreas Diefenbach; Ed Palmer; Yakup Tanriver

doi:10.1016/j.immuni.2014.06.018

The transcription factor T-bet is induced by IL-15 and thymic agonist selection and controls CD8αα(+) intraepithelial lymphocyte development

Immunity. 2014 Aug 21;41(2):230-43. doi: 10.1016/j.immuni.2014.06.018.

Affiliations

¹ Institute of Medical Microbiology and Hygiene, University of Freiburg Medical Center, 79104 Freiburg, Germany; Department of Internal Medicine IV, University of Freiburg Medical Center, 79106 Freiburg, Germany.
² Institute of Medical Microbiology and Hygiene, University of Freiburg Medical Center, 79104 Freiburg, Germany; Institute of Medical Microbiology and Hygiene, University of Mainz Medical Center, 55131 Mainz, Germany.
³ Institute of Medical Microbiology and Hygiene, University of Freiburg Medical Center, 79104 Freiburg, Germany; Institute of Medical Microbiology and Hygiene, University of Mainz Medical Center, 55131 Mainz, Germany; International Max Planck Research School for Molecular and Cellular Biology, 79108 Freiburg, Germany.
⁴ Institute of Medical Microbiology and Hygiene, University of Freiburg Medical Center, 79104 Freiburg, Germany; Department of Internal Medicine IV, University of Freiburg Medical Center, 79106 Freiburg, Germany; Faculty of Biology, 79104 Freiburg, Germany.
⁵ Department of Internal Medicine IV, University of Freiburg Medical Center, 79106 Freiburg, Germany; BIOSS Center of Biological Signalling Studies, 79104 Freiburg, Germany.
⁶ Institute of Medical Microbiology and Hygiene, University of Mainz Medical Center, 55131 Mainz, Germany.
⁷ Laboratory of Transplantation Immunology, Departments of Biomedicine and Nephrology, University Hospital Basel, 4031 Basel, Switzerland.
⁸ Institute of Medical Microbiology and Hygiene, University of Freiburg Medical Center, 79104 Freiburg, Germany; Department of Internal Medicine IV, University of Freiburg Medical Center, 79106 Freiburg, Germany. Electronic address: yakup.tanriver@uniklinik-freiburg.de.

PMID: 25148024
DOI: 10.1016/j.immuni.2014.06.018

Abstract

CD8αα(+) intraepithelial lymphocytes (IELs) are instrumental in maintaining the epithelial barrier in the intestine. Similar to natural killer cells and other innate lymphoid cells, CD8αα(+) IELs constitutively express the T-box transcription factor T-bet. However, the precise role of T-bet for the differentiation or function of IELs is unknown. Here we show that mice genetically deficient for T-bet lacked both TCRαβ(+) and TCRγδ(+) CD8αα(+) IELs and thus are more susceptible to chemically induced colitis. Although T-bet was induced in thymic IEL precursors (IELPs) as a result of agonist selection and interleukin-15 (IL-15) receptor signaling, it was dispensable for the generation of IELPs. Subsequently, T-bet was required for the IL-15-dependent activation, differentiation, and expansion of IELPs in the periphery. Our study reveals a function of T-bet as a central transcriptional regulator linking agonist selection and IL-15 signaling with the emergence of CD8αα(+) IELs.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
CD4-Positive T-Lymphocytes / immunology
CD8 Antigens / biosynthesis*
CD8-Positive T-Lymphocytes / immunology
Cell Differentiation / immunology
Colitis / chemically induced
Colitis / immunology
Epithelial Cells / immunology
Interleukin-15 / genetics*
Interleukin-15 / immunology
Intestinal Mucosa / cytology
Intestinal Mucosa / immunology
Intestines / cytology
Intestines / immunology
Mice
Mice, Inbred C57BL
Mice, Knockout
Receptors, Antigen, T-Cell, alpha-beta / genetics*
Receptors, Antigen, T-Cell, gamma-delta / genetics*
Receptors, Interleukin-15 / immunology
Signal Transduction / immunology
T-Box Domain Proteins / biosynthesis
T-Box Domain Proteins / genetics*

Substances

CD8 Antigens
CD8 antigen, alpha chain
Interleukin-15
Receptors, Antigen, T-Cell, alpha-beta
Receptors, Antigen, T-Cell, gamma-delta
Receptors, Interleukin-15
T-Box Domain Proteins
T-box transcription factor TBX21