8Weeks0LogOur laboratory tries to understand how cytokines contribute to T and B -338KO-Disease(D)KO-Heathy(H)1012253Stat3flox/floxK5-cre（KO)cell immunity, mainly focusing on infectious virus immunity and innate and acquired immunity in allergic responses.Signal transducer and activator of transcription 3 (STAT) is a critical cyto-kine signaling molecule that is activated in response to several gp130-related cytokines. STAT3 provides a crucial signal in controlling epithelial prolifera-tion in various tissues, including the skin. A dominant-negative mutation of the STAT3 gene causes atopic dermatitis (AD)-like dermatitis in Hyper IgE syndrome patients. However, how STAT3 defects in the skin lead to AD re-mains poorly understood. We established Stat3flox/flox K5-cre mice and found that STAT3 signaling is required to maintain skin homeostasis by negatively controlling the expression of hair follicle-specific keratin genes. These STAT3-dependent keratin genes play a critical role in maintaining the homeostasis of skin, which is constantly exposed to microorganisms. Indeed, the AD onset is observed in specific pathogen-free but not in germ-free conditions. Therefore, the STAT3-dependent process influenced the skin barrier penetration and skin microbes. Our results indicated that STAT3 activation by skin microbes plays a vital role in maintaining skin homeostasis and barrier function throughout life (Figure).The adaptive immune response to virus infection is multifaceted and com-plex. Vaccines are the best available countermeasure against virus infection. However, viruses escape from vaccine-induced immune responses owing to their high mutation rate and antigenic flexibility. We have reported that inacti-vated vaccines against the influenza A virus (IAV) induce IgG2-dominant reac-tions, but their effectiveness is narrow. In contrast, the IgG responses caused by natural infection with IAV were relatively broader compared to the inactivated vaccine. We demonstrated that the broadly neutralizing antibodies (bnAbs) tar-geted the conserved conformational epitopes of hemagglutinin and that these bnAbs pre-existed in the germline compartment. We also revealed that the ef-ficient generation of the bnAbs largely depends on IL-4 from TFH cells in the germinal center. Therefore, we conclude that attenuated live-virus vaccination is a valuable strategy for producing effective bnAbs.Figure: Role of STAT3 signaling in maintaining homeostasis of skin keratinocytesLeft: skin transcriptome was analyzed in K5-cre (control) and Stat3 KO mice, and the KO group were further di-vided into two groups based on disease onset as follows: healthy with no dermatitis (KO-H) and diseased mice (KO-D). Heat mapping of enhanced gene in KO mice and Gene enrichment analysis. The results indicated strong association with hair and skin development and function. Right: A schematic diagram shows that STAT3 signaling is required for balancing type I and II Keratin genes expression, which is disturbed by microorgan-isms, to maintain skin homeostasis.Recent Major PublicationsMiyauchi K, Ki S, Ukai M, Suzuki Y, Inoue K, Suda W, Matsui T, Ito Y, Honda K, Koseki H, Ohara O, Tanaka JR. Okada-Hatakeyama M, Kubo M. Essential role of STAT3 signaling in hair follicle homeostasis. Front Immunol 12, 663177 (2021)Miyauchi K, Adachi Y, Tonouchi K, Yajima T, Harada Y, Fukuyama H, Deno S, Iwakura Y, Yoshimura A, Hasegawa H, Yugi K, Fujii S, Ohara O, Takahashi Y, and Kubo M. In-fluenza virus infection expands the breadth of antibody responses through IL-4 signal in B cells. Nat Commun 12, 3789 (2021)Wang F, Trier AM, Li F, Kim S, Chen Z, Chai JN, Mack MR, Morrison SA, Hamilton JD, Baek J, Yang TB, Ver Heul AM, Xie AZ, Dong X, Kubo M, Hu H, Hsieh CS, Dong X, Liu Q, Margolis DJ, Ardeleanu M, Miller MJ, Kim BS. A basophil-neuronal axis promotes itch. Cell 184, 422-440.e17 (2021)Invited presentationsSasaki T, Kubo M. “A pathogenic role of IL-13 in anaphy-laxis” The 50th Annual Meeting of the Japanese Society for Immunology (Nara, Japan) December 2021Kubo M. “Different immunodominance of influenza virus between infection and vaccination” The 5th Inter-national Immunological Memory and Vaccine Forum (Berlin, Germany/Online) April 2021Laboratory for Cytokine RegulationTeam Leader: Masato Kubo
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