Identification of a transcription factor that controls cytotoxic T lymphocyte in a murine model of GVHD

• Project/Area Number: 24591662
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Dermatology
• Research Institution: Nara Medical University
• Principal Investigator: MIYAGAWA Fumi 奈良県立医科大学, 医学部, 助教 (00346024)
• Co-Investigator(Kenkyū-buntansha): ASADA Hideo 奈良県立医科大学, 皮膚科, 教授 (60252681)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: CD8 T cell / effector function / IL-15 / gamma c cytokine / TCR / GVHD / 国際情報交換 / CD8 T細胞 / エフェクター機能 / アメリカ合衆国 / CD8 T 細胞

Outline of Final Research Achievements

We previously reported that γc-cytokines, especially IL-15, play a critical role in determining whether or not CD8 cells exert cytotoxic activity in an experimental GVHD mouse model. We then hypothesized that cooperation between γc-cytokine and TCR/co-stimulation signaling is critical in enabling the transition of naive CD8 T cells into effector cells. In this study, we demonstrated that the transcription factor interferon regulatory factor 8 (IRF8) is persistently activated by these two signals in CD8 T cells. Blocking these signaling pathways by either a ZAP70 inhibitor or a Jak3 inhibitor abrogated IRF8 upregulation and inhibited effector differentiation in CD8 T cells. In an experimental GVHD mouse model, IRF8 deficient CD8 T cells failed to differentiate into cytotoxic T cells, causing reduced pathology. Together, our work shows that IRF8 integrates the TCR/co-stimulation and γc-cytokine signaling pathways and drives transition of naive CD8 T cells to effector cells.

Research Products

• [Journal Article] Usefulness of ultrasonography for rapidly diagnosing cutaneous sinus tracts of dental origin (2014)
  • Author(s): Shobatake C, Miyagawa F, Fukumoto T, Hirai T, Kobayashi N, Asada H
  • Journal Title: Eur J Dermatol Volume: 24 Issue: 6 Pages: 683-687
  • DOI: 10.1684/ejd.2014.2441
  • Peer Reviewed
• [Journal Article] Elevated serum thymus and activation-regulated chemokine (TARC/CCL17) relates to reactivation of human herpesvirus 6 in drug reactions with eosinophilia and systemic symptoms (DRESS)/ drug-induced hypersensitivity syndrome (DIHS). (2014)
  • Author(s): Ogawa K, Morito H, Hasegawa A, Miyagawa F, Kobayashi N, Watanabe H, Sueki H, Tohyama M, Hashimoto K, Kano Y, Shiohara T, Ito K, Fujita H, Aihara M, Asada H
  • Journal Title: Br J Dermatol Volume: - Issue: 2 Pages: 425-427
  • DOI: 10.1111/bjd.12948
  • Peer Reviewed / Open Access
• [Journal Article] Identification of thymus and activation-regulated chemokine (TARC/CCL17) as a potential marker for early indication of disease and prediction of disease activity in drug-induced hypersensitivity syndrome (DIHS)/ drug rash with eosinophilia and systemic symptoms (DRESS). (2013)
  • Author(s): Ogawa K, Morito H, Hasegawa A, Daikoku N, Miyagawa F, Okazaki A, Fukumoto T, Kobayashi N, Kasai T, Watanabe H, Sueki H, Iijima M, Tohyama M, Hashimoto K, Asada H
  • Journal Title: J Dermatol Sci Volume: 69 Issue: 1 Pages: 38-43
  • DOI: 10.1016/j.jdermsci.2012.10.002
  • Peer Reviewed
• [Journal Article] Successful treatment of diffuse normolipemic plane xanthoma with probucol. (2013)
  • Author(s): Miyagawa F, Fukumoto T, Kobayashi N, Asada H
  • Journal Title: Case Rep Dermatol Volume: 5 Issue: 2 Pages: 148-151
  • DOI: 10.1159/000351682
  • Peer Reviewed
• [Journal Article] CD8+ primary cutaneous peripheral T-cell lymphoma in an 18-year-old woman. (2013)
  • Author(s): Miyagawa F, Fukumoto T, Yurugi S, Nakamine H, Asada H
  • Journal Title: J Dermatol Volume: 40 Pages: 571-572
  • Peer Reviewed
• [Journal Article] Identification of CD3+CD4-CD8- T cells as potential regulatory cells in an experimental murine model of graft-versus-host skin disease (GVHD). (2013)
  • Author(s): Miyagawa F, Okiyama N, Villarroel V, Katz SI
  • Journal Title: J Invest Dermatol Volume: 133 Issue: 11 Pages: 2538-2545
  • DOI: 10.1038/jid.2013.212
  • Peer Reviewed
• [Journal Article] Soluble peptide treatment reverses CD8 T-cell-induced disease in a mouse model of spontaneous tissue-selective autoimmunity (2012)
  • Author(s): Paek SY, Miyagawa F, Zhang H, Linton JT, Hoover SB, Simpson RM, Katz SI
  • Journal Title: J Invest Dermatol Volume: 132 Issue: 3 Pages: 677-686
  • DOI: 10.1038/jid.2011.347
  • Peer Reviewed
• [Journal Article] Interferon regulatory factor 8 integrates T-cell receptor and cytokine-signaling pathways and drives effector differentiation of CD8 T cells (2012)
  • Author(s): Miyagawa F, Zhang H, Terunuma A, Ozato K, Tagaya Y, Katz SI
  • Journal Title: Proc Natl Acad USA Volume: 109 Issue: 30 Pages: 12123-12128
  • DOI: 10.1073/pnas.1201453109
  • Peer Reviewed
• [Presentation] Involvement of HHV-6 infection in renal damage associated with DIHS (2014)
  • Author(s): Miyashita K, Shobatake C, Miyagawa F, Kobayashi N, Ommori R, Asada H
  • Organizer: The 39th Annual Meeting of the Japanese Society for Investigative Dermatology
  • Place of Presentation: Osaka, Japan
  • Year and Date: 2014-12-12 – 2014-12-14
• [Presentation] IRF7 controls the production of autoantibodies against the DNA- and RNA-containing autoantigens in murine lupus (2014)
  • Author(s): Miyagawa F, Asada H
  • Organizer: The 39th Annual Meeting of the Japanese Society for Investigative Dermatology
  • Place of Presentation: Osaka, Japan
  • Year and Date: 2014-12-12 – 2014-12-14
• [Presentation] Involvement of HHV-6 infection in renal damage associated with DIHS/DRESS (2014)
  • Author(s): Miyashita K, Shobatake C, Nishimura T, Ogawa K, Miyagawa F, Kobayashi N, Ommori R, Asada H
  • Organizer: The 44th Annual Meeting of the European Society for Dermatological Research
  • Place of Presentation: Copenhagen, Denmark
  • Year and Date: 2014-09-10 – 2014-09-13
• [Presentation] A case of acute renal failure related to DIHS due to TMP/SMX (2014)
  • Author(s): Miyashita K, Shoubatake C, Miyagawa F, Kobayashi N, Onmori R, Yonekawa S, Tanabe K, Kawate K, Morita K, Asada H
  • Organizer: The 39th Annual International Herpesvirus workshop
  • Place of Presentation: Kobe, Japan
  • Year and Date: 2014-07-19 – 2014-07-23
• [Presentation] A role of IRF7 in the pathogenesis of SLE (2014)
  • Author(s): Miyagawa F, Asada H
  • Organizer: The 73rd Annual Meeting of the Society for Investigative Dermatology
  • Place of Presentation: Albuquerque, New Mexico, USA
  • Year and Date: 2014-05-07 – 2014-05-10
• [Presentation] Dynamics of Chemokines in Severe Drug Hypersensitivity (2014)
  • Author(s): Asada H, Ogawa K, Hasegawa A, Miyagawa F, Watanabe H, Sueki H, Tohyama M, Hashimoto K, Kano Y, Shiohara T, Fujita H, Aihara M
  • Organizer: The 6th Drug Hypersensitivity Meeting
  • Place of Presentation: Bern, Switzerland
  • Year and Date: 2014-04-09 – 2014-04-12
• [Presentation] IRF8 and IRF4 work cooperatively in CD8 T cell effector differentiation. (2013)
  • Author(s): Miyagawa F, Zhang H, Katz SI, Asada H
  • Organizer: International Investigative Dermatology
  • Place of Presentation: Edinburgh, Scotland
• [Presentation] IRF8 controls activation-induced cell death on CD8 T cells by regulating Bcl2 (2012)
  • Author(s): Miyagawa F, Tagaya Y, Ozato K, Katz SI
  • Organizer: Society for Investigative Dermatology
  • Place of Presentation: North Carolina