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Suppression of Th2 and Tfh immune reactions by Nr4a receptors in mature T reg cells

Significance Statement

Immune systems protect our body from threats by various infectious pathogens, including bacteria, virus, helminth, and fungi. In the immune systems, CD4+ helper T cells (Th) play central roles to exert appropriate immune reactions to such innumerable sorts of pathogens. However, if the function of Th are wrongly directed to self-antigens or non-harmful antigens, including pollens, food antigens, and commensals, it will be concluded to serious inflammatory diseases like autoimmune diseases and allergies. On the other hand, immune system has an important cell subset, regulatory T (Treg) cells, which suppress such wrong immune reactions. Treg cells have been known to be critical in suppression of inflammatory diseases, however, how Treg cell lineage was properly maintained in our body had not been clarified in depth yet. In this study, we discovered that Nr4a family of nuclear orphan receptors play critical roles in the maintenance of the Treg cell lineage. Nr4a-deficient Treg cells showed a global reduction of Treg cell-associated gene expressions, compared with those in wildtype Treg cells. Although wildtype Treg cells properly suppressed immune reactions elicited by Th2 and Tfh cells, it was revealed that Nr4a-deficient Treg cells have lost such suppressive activities. We also found that Nr4a-deficient Treg cells aberrantly convert to cells which have characteristics of inflammatory Th cells. Mice in which Nr4a factors were deleted specifically in Treg cells develop symptoms including allergic asthma and autoimmune diseases. Collectively, our work revealed that Nr4a factors play essential roles in Treg cell biology, thus present attractive therapeutic targets for treatment of various immune disorders, including atopic allergies and asthma. 

About The Author

Dr. Takashi Sekiya received his Bachelor of Science degree in 1999 from University of Tokyo. He obtained his Ph.D. from Graduate School of Agricultural and Life Sciences, The University of Tokyo in 2004. Then, he moved to Fox Chase Cancer Center as a postdoctoral fellow at Dr. Ken Zaret’s laboratory. In 2008, he moved back to Japan, and joined Dr. Akihiko Yoshimura’s lab in Keio University School of Medicine, there he has been working on mechanisms of immune tolerance, focusing on developmental programs of CD4 T cells. 

Suppression of Th2 and Tfh immune reactions by Nr4a receptors in mature T reg cells. Global Medical Discovery

Journal Reference

J Exp Med. 2015;212(10):1623-40.

Sekiya T1, Kondo T2, Shichita T2, Morita R2, Ichinose H3, Yoshimura A4.

Show Affiliations
  1. Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan [email protected]@z7.keio.jp.
  2. Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
  3. Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Kanagawa 226-8501, Japan.
  4. Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan Japan Science and Technology Agency (JST), Core Research for Evolutional Science and Technology, Chiyoda-ku, Tokyo 102-0075, Japan [email protected]@z7.keio.jp.

Abstract

Regulatory T (T reg) cells are central mediators of immune suppression. As such, T reg cells are characterized by a distinct pattern of gene expression, which includes up-regulation of immunosuppressive genes and silencing of inflammatory cytokine genes. Although an increasing number of transcription factors that regulate T reg cells have been identified, the mechanisms by which the T reg cell-specific transcriptional program is maintained and executed remain largely unknown. The Nr4a family of nuclear orphan receptors, which we recently identified as essential for the development of T reg cells, is highly expressed in mature T reg cells as well, suggesting that Nr4a factors play important roles even beyond T reg cell development. Here, we showed that deletion of Nr4a genes specifically in T reg cells caused fatal systemic immunopathology. Nr4a-deficient Treg cells exhibited global alteration of the expression of genes which specify the T reg cell lineage, including reduction of Foxp3 and Ikzf4. Furthermore, Nr4a deficiency abrogated T reg cell suppressive activities and accelerated conversion to cells with Th2 and follicular helper T (Tfh) effector-like characteristics, with heightened expression of Th2 and Tfh cytokine genes. These findings demonstrate that Nr4a factors play crucial roles in mature T reg cells by directly controlling a genetic program indispensable for T reg cell maintenance and function.

© 2015 Sekiya et al.

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