The interleukin-15 system suppresses T cell-mediated autoimmunity by regulating negative selection and nT(H)17 cell homeostasis in the thymus

Mau-Sheng Hou; Shih-Ting Huang; Ming-Han Tsai; Ching-Cheng Yen; Yein-Gei Lai; Yae-Huei Liou; Chih-Kung Lin; Nan-Shih Liao

doi:10.1016/j.jaut.2014.11.003

The interleukin-15 system suppresses T cell-mediated autoimmunity by regulating negative selection and nT(H)17 cell homeostasis in the thymus

J Autoimmun. 2015 Jan:56:118-29. doi: 10.1016/j.jaut.2014.11.003. Epub 2014 Dec 10.

Authors

Mau-Sheng Hou¹, Shih-Ting Huang², Ming-Han Tsai³, Ching-Cheng Yen⁴, Yein-Gei Lai³, Yae-Huei Liou³, Chih-Kung Lin⁵, Nan-Shih Liao⁶

Affiliations

¹ Molecular Cell Biology, Taiwan International Graduate Program, Academia Sinica and Graduate Institute of Life Science, National Defense Medical Center, Taipei 115, Taiwan; Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan.
² Graduate Institute of Life Science, National Defense Medical Center, Taipei 115, Taiwan; Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan.
³ Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan.
⁴ Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan; Institute of Genome Sciences, National Yang-Ming University, Taipei 112, Taiwan.
⁵ Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan.
⁶ Molecular Cell Biology, Taiwan International Graduate Program, Academia Sinica and Graduate Institute of Life Science, National Defense Medical Center, Taipei 115, Taiwan; Graduate Institute of Life Science, National Defense Medical Center, Taipei 115, Taiwan; Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan. Electronic address: mbfelix@imb.sinica.edu.tw.

PMID: 25500198
DOI: 10.1016/j.jaut.2014.11.003

Abstract

The interleukin-15 (IL-15) system is important for regulating both innate and adaptive immune responses, however, its role in autoimmune disease remained unclear. Here we found that Il15(-/-) and Il15ra(-/-) mice spontaneously developed late-onset autoimmune phenotypes. CD4(+) T cells of the knockout mice showed elevated autoreactivity as demonstrated by the induction of lymphocyte infiltration in the lacrimal and salivary glands when transferred into nude mice. The antigen-presenting cells in the thymic medullary regions expressed IL-15 and IL-15Rα, whose deficiency resulted in insufficient negative selection and elevated number of natural IL-17A-producing CD4(+) thymocytes. These findings reveal previously unknown functions of the IL-15 system in thymocyte development, and thus a new layer of regulation in T cell-mediated autoimmunity.

Keywords: IL-15; IL-15Rα; Negative selection; Thymus; nT(H)17.

Publication types

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

MeSH terms

Animals
Antigen-Presenting Cells / immunology
Antigen-Presenting Cells / metabolism
Autoantibodies / blood
Autoantibodies / immunology
Autoimmunity* / genetics
CD4-Positive T-Lymphocytes / immunology
CD4-Positive T-Lymphocytes / metabolism
Clonal Selection, Antigen-Mediated
Female
Gene Expression
Homeostasis*
Immunophenotyping
Interleukin-15 / deficiency
Interleukin-15 / genetics
Interleukin-15 / metabolism*
Interleukin-15 Receptor alpha Subunit / deficiency
Interleukin-15 Receptor alpha Subunit / genetics
Lymph Nodes / immunology
Lymph Nodes / pathology
Lymphocyte Activation / genetics
Lymphocyte Activation / immunology
Mice
Mice, Knockout
Phenotype
Radiation Tolerance / genetics
Salivary Glands / immunology
Salivary Glands / pathology
T-Lymphocyte Subsets / immunology*
T-Lymphocyte Subsets / metabolism*
Th17 Cells / immunology*
Th17 Cells / metabolism*
Thymocytes / immunology
Thymocytes / metabolism
Thymus Gland* / immunology
Thymus Gland* / metabolism
Thymus Gland* / pathology

Substances

Autoantibodies
Interleukin-15
Interleukin-15 Receptor alpha Subunit