Research activity information

• Apr. 2019 Legend Research Grant Program 2018


• Feb. 2019 第35回井上研究奨励賞

• Purine salvage pathway protects CD8+ T cells from metabolic stress

  Masaki Tajima, He Hao, Baihao Zhang, Yuta Matsuoka, Kazuhiro Sonomura, Koshi Imami, Yosuke Isobe, Rae Maeda, Yu-Hsien Lin, Akihiro Shimba, Ryoma Kato, Pedro Henrique Costa Cruz, Sayaka Washizu, Yosuke Ikejiri, Akiyo Morinibu, Clive Steven Barker, Jun Seita, Yibo Wu, Satomi Ito, Seiko Narushima, Rei Nakano, Mikako Maruya, Wakana Kobayashi, Sai Shanmukha Priya Narayanan, Jumana Shaheen, Hiroyuki Neyama, Ken-ichi Yamada, Makoto Arita, Yuki Sugiura, Sidonia Fagarasan

  Springer Science and Business Media LLC, Apr. 2026, Nature Immunology, 27(5) (5), 1026 - 1038

  Scientific journal


• PRR enhances anti-tumor immunity and suppresses colitis by promoting the development and survival of naive T and iNKT cells

  Akihiro Shimba, Satoru Munakata, Shinya Abe, Guangwei Cui, Ryoma Kato, Masaki Miyazaki, Atsuhiro Ichihara, Koichi Ikuta

  The (pro)renin receptor (PRR) is a multifunctional transmembrane protein that enhances β-catenin/TCF1 signaling and V-ATPase-mediated lysosomal acidification. Emerging evidence indicates that it may also regulate potential roles in regulating T cell development, survival, and immune responses. Here, we demonstrated that PRR promotes the maturation and survival of T cells within the thymus. In particular, PRR-deficient mice exhibited a significant reduction in iNKT cells in the thymus and periphery. PRR promoted the energy synthesis process in mitochondria, as evidenced by increased mitochondrial amount and membrane potential. This phenomenon was accompanied by an increase in TCF1 expression and lysosomal acidification. Furthermore, PRR enhanced the survival of naive T and iNKT cells in the periphery, while simultaneously suppressing inflammatory cytokine-producing T cells, thereby preventing colitis. In contrast, PRR enhanced resistance against tumor growth by increasing the number of tumor-infiltrating Th1 and iNKT cells, which in turn promoted NK cell recruitment. This study indicates that PRR is critical for supporting T cell maintenance, suppressing excessive inflammation, and enhancing anti-tumor immunity.

  Frontiers Media SA, Dec. 2025, Frontiers in Immunology, 16

  Scientific journal


• Stress-induced glucocorticoids enhance acute inflammation by promoting the differentiation of Th17 cells

  Akihiro Shimba, Guangwei Cui, Shinya Abe, Keiji Hirota, Eiji Miyauchi, Daichi Takami, Shizue Tani-ichi, Ryoma Kato, Masaki Tajima, Toru Kanahashi, Masaki Miyazaki, Hans-Reimer Rodewald, Hiroyuki Yoshitomi, Hideki Ueno, Hiroshi Ohno, Koichi Ikuta

  Elsevier BV, Aug. 2025, Cell Reports, 44(8) (8), 116093 - 116093

  Scientific journal


• IL-7Rα signaling in regulatory T cells of adipose tissue is essential for systemic glucose homeostasis.

  Shizue Tani-Ichi, Shinya Abe, Hitoshi Miyachi, Satsuki Kitano, Akihiro Shimba, Aki Ejima, Takahiro Hara, Guangwei Cui, Tomonobu Kado, Shohei Hori, Kazuyuki Tobe, Koichi Ikuta

  Regulatory T cells (Tregs) mediate tissue homeostasis and repair. The function of the interleukin-7 receptor α (IL-7Rα) in nonlymphoid tissue Tregs is still unknown, although low expression of IL-7Rα is a widely accepted marker for Tregs. Here, we show that IL-33R (ST2)-expressing Tregs in the visceral adipose tissue (VAT) express the IL-7Rα at high levels. Treg-specific IL-7Rα-deficient mice exhibited reduced adipose ST2+ Tregs and impaired glucose tolerance, whereas IL-7Rα was dispensable for Tregs in lymphoid tissues. Mice deficient in thymic stromal lymphopoietin (TSLP), an additional ligand for IL-7Rα, displayed a modest decrease in adipose ST2+ Tregs and a reduced accumulation of adipose eosinophils, accompanied by slightly impaired glucose tolerance. In the VAT, mesothelial cells expressed IL-7, whereas adipose stem cells and folate receptor β-expressing tissue-resident macrophages expressed TSLP. Thus, this study indicates the significance of IL-7Rα signaling in the maintenance of VAT Tregs and glucose homeostasis, revealing a novel role for IL-7 and TSLP in immunometabolism.

  Apr. 2025, Journal of immunology (Baltimore, Md. : 1950), 214(4) (4), 666 - 679, English, International magazine

  Scientific journal


• The transcription factor RORα is required for the development of type 1 innate lymphoid cells in adult bone marrow

  Shinya Abe, Moe Kagao, Takuma Asahi, Ryoma Kato, Shizue Tani-ichi, Akihiro Shimba, Riki Ishibashi, Hitoshi Miyachi, Satsuki Kitano, Masaki Miyazaki, Hans-Reimer Rodewald, Fumiko Toyoshima, Koichi Ikuta

  Abstract Type 1 innate lymphoid cells (ILC1s) respond to infections and tumors by producing IFN-γ. Although RAR-related orphan receptor α (RORα) is required for ILC2s and some ILC3s, its role in ILC1 development remains controversial. To investigate the role of RORα in ILC1s, we analyzed bone marrow (BM) chimeras of RORα-deficient mice. ILC1s derived from RORα-deficient BM cells were significantly reduced in various tissues, including the intestine, indicating a hematopoietic cell-intrinsic need for RORα in ILC1 development. Developmental stage–specific RORα-deficient mice showed a decrease in adult liver and BM IL-7R+ ILC1s and an increase in BM NK cells, whereas fetal liver ILC1s and adult liver IL-7R− ILC1s remained unchanged. Furthermore, RORα is primarily required for IL-7R+ precursor stages and partially affects small intestine ILC1 after differentiation. This study suggests that RORα promotes ILC1 differentiation while suppressing NK cell differentiation at the ILC precursor stage in the adult BM.

  Oxford University Press (OUP), Mar. 2025, The Journal of Immunology

  Scientific journal


• A Chimeric IL-7Rα/IL-2Rβ Receptor Promotes the Differentiation of T Cell Progenitors into B Cells and Type 2 Innate Lymphoid Cells.

  Akihiro Shimba, Shizue Tani-Ichi, Kyoko Masuda, Guangwei Cui, Satoru Munakata, Shinya Abe, Satsuki Kitano, Hitoshi Miyachi, Hiroshi Kawamoto, Koichi Ikuta

  IL-7 and IL-2 are evolutionarily related cytokines that play critical roles in the development and expansion of immune cells. Although both IL-7R and IL-2R activate similar signaling molecules, whether their signals have specific or overlapping functions during lymphocyte differentiation remains unclear. To address this question, we generated IL-7R α-chain (IL-7Rα)/IL-2R β-chain (IL-24β) (72R) knock-in mice expressing a chimeric receptor consisting of the extracellular domain of IL-7Rα and the intracellular domain of IL-2Rβ under the control of the endogenous IL-7Rα promoter. Notably, this 72R receptor induced higher levels of STAT5 and Akt phosphorylation in T cells. In the periphery of 72R mice, the number of T cells, B cells, and type 2 innate lymphoid cells (ILC2s) was increased, whereas early T cell progenitors and double-negative 2 thymocytes were reduced in the thymus. In addition, cell proliferation and Notch signaling were impaired in the early thymocytes of 72R mice, leading to their differentiation into thymic B cells. Interestingly, ILC2s were increased in the thymus of 72R mice. Early T cell progenitors from 72R mice, but not from wild-type mice, differentiated into NK cells and ILC2-like cells when cocultured with a thymic stromal cell line. Thus, this study indicates that the chimeric 72R receptor transduces more robust signals than the authentic IL-7Rα, thereby inducing the alternative differentiation of T cell progenitors into other cell lineages. This suggests that cytokine receptors may provide instructive signals for cell fate decisions.

  Lead, Aug. 2024, Journal of immunology (Baltimore, Md. : 1950), English, International magazine

  Scientific journal


• A RORE-dependent Intronic Enhancer in the IL-7 Receptor-α Locus Controls Glucose Metabolism via Vγ4+ γδT17 Cells

  Shizue Tani-ichi, David Obwegs, Alice Yoshikawa, Hitomi Watanabe, Satsuki Kitano, Aki Ejima, Shinya Hatano, Hitoshi Miyachi, Guangwei Cui, Akihiro Shimba, Shinya Abe, Shohei Hori, Gen Kondoh, Sagar, Yasunobu Yoshikai, Koichi Ikuta

  Abstract The IL-7R regulates the homeostasis, activation, and distribution of T cells in peripheral tissues. Although several transcriptional enhancers that regulate IL-7Rα expression in αβ T cells have been identified, enhancers active in γδ T cells remain unknown. In this article, we discovered an evolutionarily conserved noncoding sequence (CNS) in intron 2 of the IL-7Rα-chain (IL-7Rα) locus and named this region CNS9. CNS9 contained a conserved retinoic acid receptor-related orphan receptor (ROR)–responsive element (RORE) and exerted RORγt-dependent enhancer activity in vitro. Mice harboring point mutations in the RORE in CNS9 (CNS9-RORmut) showed reduced IL-7Rα expression in IL-17–producing Vγ4+ γδ T cells. In addition, the cell number and IL-17A production of Vγ4+ γδ T cells were reduced in the adipose tissue of CNS9-RORmut mice. Consistent with the reduction in IL-17A, CNS9-RORmut mice exhibited decreased IL-33 expression in the adipose tissue, resulting in fewer regulatory T cells and glucose intolerance. The CNS9-ROR motif was partially responsible for IL-7Rα expression in RORγt+ regulatory T cells, whereas IL-7Rα expression was unaffected in RORγt-expressing Vγ2+ γδ T cells, Th17 cells, type 3 innate lymphoid cells, and invariant NKT cells. Our results indicate that CNS9 is a RORΕ-dependent, Vγ4+ γδ T cell–specific IL-7Rα enhancer that plays a critical role in adipose tissue homeostasis via regulatory T cells, suggesting that the evolutionarily conserved RORΕ in IL-7Rα intron 2 may influence the incidence of type 2 diabetes.

  The American Association of Immunologists, Jun. 2024, The Journal of Immunology, 213(3) (3), 283 - 295

  Scientific journal


• Hematopoietic cell-derived IL-15 supports NK cell development in scattered and clustered localization within the bone marrow.

  Shinya Abe, Takuma Asahi, Takahiro Hara, Guangwei Cui, Akihiro Shimba, Shizue Tani-Ichi, Kohei Yamada, Kazuko Miyazaki, Hitoshi Miyachi, Satsuki Kitano, Naotoshi Nakamura, Junichi Kikuta, Alexis Vandenbon, Masaki Miyazaki, Ryo Yamada, Toshiaki Ohteki, Masaru Ishii, Veronika Sexl, Takashi Nagasawa, Koichi Ikuta

  Natural killer (NK) cells are innate immune cells critical for protective immune responses against infection and cancer. Although NK cells differentiate in the bone marrow (BM) in an interleukin-15 (IL-15)-dependent manner, the cellular source of IL-15 remains elusive. Using NK cell reporter mice, we show that NK cells are localized in the BM in scattered and clustered manners. NK cell clusters overlap with monocyte and dendritic cell accumulations, whereas scattered NK cells require CXCR4 signaling. Using cell-specific IL-15-deficient mice, we show that hematopoietic cells, but not stromal cells, support NK cell development in the BM through IL-15. In particular, IL-15 produced by monocytes and dendritic cells appears to contribute to NK cell development. These results demonstrate that hematopoietic cells are the IL-15 niche for NK cell development in the BM and that BM NK cells are present in scattered and clustered compartments by different mechanisms, suggesting their distinct functions in the immune response.

  Sep. 2023, Cell reports, 113127 - 113127, English, International magazine

  Scientific journal


• CD45 alleviates airway inflammation and lung fibrosis by limiting expansion and activation of ILC2s.

  Guangwei Cui, Akihiro Shimba, Jianshi Jin, Nozomi Hojo, Takuma Asahi, Shinya Abe, Aki Ejima, Shinri Okada, Keizo Ohira, Ryoma Kato, Shizue Tani-Ichi, Ryo Yamada, Takashi Ebihara, Katsuyuki Shiroguchi, Koichi Ikuta

  Group 2 innate lymphoid cells (ILC2s) are critical for the immune response against parasite infection and tissue homeostasis and involved in the pathogenesis of allergy and inflammatory diseases. Although multiple molecules positively regulating ILC2 development and activation have been extensively investigated, the factors limiting their population size and response remain poorly studied. Here, we found that CD45, a membrane-bound tyrosine phosphatase essential for T cell development, negatively regulated ILC2s in a cell-intrinsic manner. ILC2s in CD45-deficient mice exhibited enhanced proliferation and maturation in the bone marrow and hyperactivated phenotypes in the lung with high glycolytic capacity. Furthermore, CD45 signaling suppressed the type 2 inflammatory response by lung ILC2s and alleviated airway inflammation and pulmonary fibrosis. Finally, the interaction with galectin-9 influenced CD45 signaling in ILC2s. These results demonstrate that CD45 is a cell-intrinsic negative regulator of ILC2s and prevents lung inflammation and fibrosis via ILC2s.

  Lead, Sep. 2023, Proceedings of the National Academy of Sciences of the United States of America, 120(36) (36), e2215941120, English, International magazine

  Scientific journal


• Lung group 2 innate lymphoid cells differentially depend on local IL-7 for their distribution, activation, and maintenance in innate and adaptive immunity-mediated airway inflammation.

  Daichi Takami, Shinya Abe, Akihiro Shimba, Takuma Asahi, Guangwei Cui, Shizue Tani-Ichi, Takahiro Hara, Keishi Miyata, Masashi Ikutani, Kiyoshi Takatsu, Yuichi Oike, Koichi Ikuta

  IL-7 is a cytokine critical for the development and maintenance of group 2 innate lymphoid cells (ILC2s). ILC2s are resident in peripheral tissues such as the intestine and lung. However, whether IL-7 produced in the lung plays a role in the maintenance and function of lung ILC2s during airway inflammation remains unknown. IL-7 was expressed in bronchoalveolar epithelial cells and lymphatic endothelial cells (LECs). To investigate the role of local IL-7 in lung ILC2s, we generated two types of IL-7 conditional knockout (IL-7cKO) mice: Sftpc-Cre (SPC-Cre) IL-7cKO mice specific for bronchial epithelial cells and type 2 alveolar epithelial cells and Lyve1-Cre IL-7cKO mice specific for LECs. In steady state, ILC2s were located near airway epithelia, although lung ILC2s were unchanged in the two lines of IL-7cKO mice. In papain-induced airway inflammation dependent on innate immunity, lung ILC2s localized near bronchia via CCR4 expression, and eosinophil infiltration and type 2 cytokine production were reduced in SPC-Cre IL-7cKO mice. In contrast, in house dust mite (HDM)-induced airway inflammation dependent on adaptive immunity, lung ILC2s localized near lymphatic vessels via their CCR2 expression two weeks after the last challenge. Furthermore, lung ILC2s were decreased in Lyve1-Cre IL-7cKO mice in the HDM-induced inflammation due to decreased cell survival and proliferation. Finally, administration of anti-IL-7 antibody attenuated papain-induced inflammation by suppressing the activation of ILC2s. Thus, this study demonstrates that IL-7 produced by bronchoalveolar epithelial cells and LECs differentially controls the activation and maintenance of lung ILC2s, where they are localized in airway inflammation.

  Jul. 2023, International immunology, English, International magazine

  Scientific journal


• Liver type 1 innate lymphoid cells lacking IL-7 receptor are a native killer cell subset fostered by parenchymal niches.

  Takuma Asahi, Shinya Abe, Guangwei Cui, Akihiro Shimba, Tsukasa Nabekura, Hitoshi Miyachi, Satsuki Kitano, Keizo Ohira, Johannes M Dijkstra, Masaki Miyazaki, Akira Shibuya, Hiroshi Ohno, Koichi Ikuta

  Group 1 innate lymphoid cells (G1-ILCs), including circulating natural killer (NK) cells and tissue-resident type 1 ILCs (ILC1s), are innate immune sentinels critical for responses against infection and cancer. In contrast to relatively uniform NK cells through the body, diverse ILC1 subsets have been characterized across and within tissues in mice, but their developmental and functional heterogeneity remain unsolved. Here, using multimodal in vivo approaches including fate-mapping and targeting of the interleukin 15 (IL-15)-producing microenvironment, we demonstrate that liver parenchymal niches support the development of a cytotoxic ILC1 subset lacking IL-7 receptor (7 R- ILC1s). During ontogeny, fetal liver (FL) G1-ILCs arise perivascularly and then differentiate into 7 R- ILC1s within sinusoids. Hepatocyte-derived IL-15 supports parenchymal development of FL G1-ILCs to maintain adult pool of 7 R- ILC1s. IL-7R+ (7R+) ILC1s in the liver, candidate precursors for 7 R- ILC1s, are not essential for 7 R- ILC1 development in physiological conditions. Functionally, 7 R- ILC1s exhibit killing activity at steady state through granzyme B expression, which is underpinned by constitutive mTOR activity, unlike NK cells with exogenous stimulation-dependent cytotoxicity. Our study reveals the unique ontogeny and functions of liver-specific ILC1s, providing a detailed interpretation of ILC1 heterogeneity.

  Jun. 2023, eLife, 12, English, International magazine

  Scientific journal


• Physiological concentrations of glucocorticoids induce pathological DNA double‐strand breaks

  Salma Akter, Akihiro Shimba, Koichi Ikuta, Md. Rasel Al Mahmud, Shintaro Yamada, Hiroyuki Sasanuma, Masataka Tsuda, Masakatsu Sone, Yukio Ago, Kenichi Murai, Hisashi Tanaka, Shunichi Takeda

  Wiley, Dec. 2022, Genes to Cells, 28(1) (1), 53 - 67

  Scientific journal


• A circulating subset of iNKT cells mediates antitumor and antiviral immunity.

  Guangwei Cui, Akihiro Shimba, Jianshi Jin, Taisaku Ogawa, Yukiko Muramoto, Hitoshi Miyachi, Shinya Abe, Takuma Asahi, Shizue Tani-Ichi, Johannes M Dijkstra, Yayoi Iwamoto, Kirill Kryukov, Yuanbo Zhu, Daichi Takami, Takahiro Hara, Satsuki Kitano, Yan Xu, Hajime Morita, Moyu Zhang, Lynn Zreka, Keishi Miyata, Takashi Kanaya, Shinya Okumura, Takashi Ito, Etsuro Hatano, Yoshimasa Takahashi, Hiroshi Watarai, Yuichi Oike, Tadashi Imanishi, Hiroshi Ohno, Toshiaki Ohteki, Nagahiro Minato, Masato Kubo, Georg A Holländer, Hideki Ueno, Takeshi Noda, Katsuyuki Shiroguchi, Koichi Ikuta

  Invariant natural killer T (iNKT) cells are a group of innate-like T lymphocytes that recognize lipid antigens. They are supposed to be tissue resident and important for systemic and local immune regulation. To investigate the heterogeneity of iNKT cells, we recharacterized iNKT cells in the thymus and peripheral tissues. iNKT cells in the thymus were divided into three subpopulations by the expression of the natural killer cell receptor CD244 and the chemokine receptor CXCR6 and designated as C0 (CD244-CXCR6-), C1 (CD244-CXCR6+), or C2 (CD244+CXCR6+) iNKT cells. The development and maturation of C2 iNKT cells from C0 iNKT cells strictly depended on IL-15 produced by thymic epithelial cells. C2 iNKT cells expressed high levels of IFN-γ and granzymes and exhibited more NK cell-like features, whereas C1 iNKT cells showed more T cell-like characteristics. C2 iNKT cells were influenced by the microbiome and aging and suppressed the expression of the autoimmune regulator AIRE in the thymus. In peripheral tissues, C2 iNKT cells were circulating that were distinct from conventional tissue-resident C1 iNKT cells. Functionally, C2 iNKT cells protected mice from the tumor metastasis of melanoma cells by enhancing antitumor immunity and promoted antiviral immune responses against influenza virus infection. Furthermore, we identified human CD244+CXCR6+ iNKT cells with high cytotoxic properties as a counterpart of mouse C2 iNKT cells. Thus, this study reveals a circulating subset of iNKT cells with NK cell-like properties distinct from conventional tissue-resident iNKT cells.

  Oct. 2022, Science immunology, 7(76) (76), eabj8760, English, International magazine

  Scientific journal


• Control of immunity and allergy by steroid hormones

  Koichi Ikuta, Aki Ejima, Shinya Abe, Akihiro Shimba

  Elsevier BV, Oct. 2022, Allergology International, 71(4) (4), 432 - 436

  Scientific journal


• Androgens Alleviate Allergic Airway Inflammation by Suppressing Cytokine Production in Th2 Cells.

  Aki Ejima, Shinya Abe, Akihiro Shimba, Susumu Sato, Takuya Uehata, Shizue Tani-Ichi, Satoru Munakata, Guangwei Cui, Osamu Takeuchi, Toyohiro Hirai, Shigeaki Kato, Koichi Ikuta

  Asthma is more common in females than males after adolescence. However, the mechanism of the sex bias in the prevalence of asthma remains unknown. To test whether sex steroid hormones have some roles in T cells during development of asthma, we analyzed airway inflammation in T cell-specific androgen receptor (AR)- and estrogen receptor (ER)-deficient mice. T cell-specific AR-deficient male mice developed severer house dust mite-induced allergic airway inflammation than did control male mice, whereas T cell-specific ERα- and ERβ-deficient female mice exhibited a similar degree of inflammation as for control female mice. Furthermore, administration of dihydrotestosterone reduced cytokine production of Th2 cells from control, but not AR-deficient, naive T cells. Transfer of OT-II transgenic AR-deficient Th2 cells into wild-type mice induced severer allergic airway inflammation by OVA than transfer of control Th2 cells. Gene expression profiling suggested that the expression of genes related with cell cycle and Th2 differentiation was elevated in AR-deficient Th2 cells, whereas expression of dual specificity phosphatase (DUSP)-2, a negative regulator of p38, was downregulated. In addition, a chromatin immunoprecipitation assay suggested that AR bound to an AR motif in the 5' untranslated region of the Dusp2 gene in Th2 cells. Furthermore, the Dusp2 promoter with a wild-type AR motif, but not a mutated motif, was transactivated by dihydrotestosterone in a reporter assay. Finally, forced expression of DUSP-2 by retrovirus vector reduced IL-4 expression in Th2 cells. Thus, these results suggest that androgen signaling suppresses cytokine production of Th2 cells by inducing DUSP-2, explaining, in part, the sex bias of asthma after adolescence.

  Aug. 2022, Journal of immunology (Baltimore, Md. : 1950), 209(6) (6), 1083 - 1094, English, International magazine

  Scientific journal


• Control of immunity by glucocorticoids in health and disease

  Akihiro Shimba, Koichi Ikuta

  Springer Science and Business Media LLC, Dec. 2020, Seminars in Immunopathology, 42(6) (6), 669 - 680

  Scientific journal


• Immune-enhancing effects of glucocorticoids in response to day–night cycles and stress

  Akihiro Shimba, Koichi Ikuta

  Environmental cues such as the day–night cycle or stressors trigger the production of glucocorticoids (GCs) by the adrenal cortex. GCs are well known for their anti-inflammatory effects that suppress the production of inflammatory cytokines and induce the apoptosis of lymphocytes. Recent studies in mice, however, have revealed pro-inflammatory effects. The diurnal oscillation of GCs induces the expression of IL-7 receptor α (IL-7Rα) and C–X–C motif chemokine receptor 4 (CXCR4) at the active phase, which drives the diurnal homing of T cells into lymphoid organs. This accumulation of T cells at the active phase enhances T-cell priming against bacterial infection and antigen immunization, leading to an increase of effector CD8 T cells and antibody production. GCs induced by moderate stress trigger the homing of memory CD8 T cells into the bone marrow and support the maintenance and response of these cells. Thus, endogenous GCs have a self-defense function to enhance adaptive immune responses. By contrast, strong stress induces even higher GC levels and causes chronic inflammation and autoimmunity. Because GCs can enhance the differentiation and function of T-helper 2 (Th2) and Th17 cells, high stress-induced GC levels might enhance inflammation via Th17 cell differentiation. Overall, the positive and negative effects of GCs may regulate the balance between normal immune responses and susceptibility to infections and inflammatory diseases.

  Oxford University Press (OUP), Oct. 2020, International Immunology, 32(11) (11), 703 - 708

  Scientific journal


• Glucocorticoids Regulate Circadian Rhythm of Innate and Adaptive Immunity

  Akihiro Shimba, Koichi Ikuta

  Frontiers Media SA, Sep. 2020, Frontiers in Immunology, 11

  Scientific journal


• Intestinal epithelial cell-derived IL-15 determines local maintenance and maturation of intra-epithelial lymphocytes in the intestine.

  Yuanbo Zhu, Guangwei Cui, Eiji Miyauchi, Yuki Nakanishi, Hisa Mukohira, Akihiro Shimba, Shinya Abe, Shizue Tani-Ichi, Takahiro Hara, Hiroshi Nakase, Tsutomu Chiba, Atsuko Sehara-Fujisawa, Hiroshi Seno, Hiroshi Ohno, Koichi Ikuta

  Interleukin-15 (IL-15) is a cytokine critical for maintenance of intestinal intra-epithelial lymphocytes (IELs), especially CD8αα + IELs (CD8αα IELs). In the intestine, IL-15 is produced by intestinal epithelial cells (IECs), blood vascular endothelial cells (BECs) and hematopoietic cells. However, the precise role of intestinal IL-15 on IELs is still unknown. To address the question, we generated two kinds of IL-15 conditional knockout (IL-15cKO) mice: villin-Cre (Vil-Cre) and Tie2-Cre IL-15cKO mice. IEC-derived IL-15 was specifically deleted in Vil-Cre IL-15cKO mice, whereas IL-15 produced by BECs and hematopoietic cells was deleted in Tie2-Cre IL-15cKO mice. The cell number and frequency of CD8αα IELs and NK IELs were significantly reduced in Vil-Cre IL-15cKO mice. By contrast, CD8αα IELs were unchanged in Tie2-Cre IL-15cKO mice, indicating that IL-15 produced by BECs and hematopoietic cells is dispensable for CD8αα IELs. Expression of an anti-apoptotic factor, Bcl-2, was decreased, whereas Fas expression was increased in CD8αα IELs of Vil-Cre IL-15cKO mice. Forced expression of Bcl-2 by a Bcl-2 transgene partially restored CD8αα IELs in Vil-Cre IL-15cKO mice, suggesting that some IL-15 signal other than Bcl-2 is required for maintenance of CD8αα IELs. Furthermore, granzyme B production was reduced, whereas PD-1 expression was increased in CD8αα IELs of Vil-Cre IL-15cKO mice. These results collectively suggested that IEC-derived IL-15 is essential for homeostasis of IELs by promoting their survival and functional maturation.

  May 2020, International immunology, 32(5) (5), 307 - 319, English, International magazine

  [Refereed]

  Scientific journal


• IL-7R-Dependent Phosphatidylinositol 3-Kinase Competes with the STAT5 Signal to Modulate T Cell Development and Homeostasis.

  Guangwei Cui, Akihiro Shimba, Guangyong Ma, Kazuhiko Takahara, Shizue Tani-Ichi, Yuanbo Zhu, Takuma Asahi, Akifumi Abe, Hitoshi Miyachi, Satsuki Kitano, Takahiro Hara, Jun-Ichirou Yasunaga, Hirotsugu Suwanai, Hisakata Yamada, Masao Matsuoka, Kohjiro Ueki, Yasunobu Yoshikai, Koichi Ikuta

  T cell development and homeostasis requires IL-7R α-chain (IL-7Rα) signaling. Tyrosine Y449 of the IL-7Rα is essential to activate STAT5 and PI3K, whereas PI3K recruitment requires IL-7Rα methionine M452. How IL-7Rα activates and regulates both signaling pathways differentially remains unclear. To characterize differential signaling, we established two lines of IL-7Rα mutant mice: IL-7R-Y449F mice and IL-7R-M452L mice. IL-7R-Y449F mice showed decreased PI3K and STAT5 signals, whereas IL-7R-M452L mice showed decreased PI3K but significantly increased STAT5 signaling, owing to a competition between PI3K and STAT5 signaling through Y449 of IL-7Rα. The number of T, B, and mature innate lymphoid cells were markedly reduced in IL-7R-Y449F mice, whereas IL-7R-M452L mice showed impaired early T cell development and memory precursor effector T cell maintenance with the downregulation of transcription factor T cell factor-1. Peripheral T cell numbers increased in IL-7R-M452L mice with enhanced survival and homeostatic proliferation. Furthermore, although wild type and IL-7R-Y449F mice showed comparable Th1/Th2 differentiation, IL-7R-M452L mice exhibited impaired Th17 differentiation. We conclude that PI3K competes with STAT5 under IL-7Rα and maintains an appropriate signal balance for modulating T cell development and homeostasis. To our knowledge, this study provides a new insight into complex regulation of IL-7Rα signaling, which supports immune development and responses.

  Feb. 2020, Journal of immunology (Baltimore, Md. : 1950), 204(4) (4), 844 - 857, English, International magazine

  [Refereed]

  Scientific journal


• Chronic circadian misalignment accelerates immune senescence and abbreviates lifespan in mice.

  Hitoshi Inokawa, Yasuhiro Umemura, Akihiro Shimba, Eiryo Kawakami, Nobuya Koike, Yoshiki Tsuchiya, Munehiro Ohashi, Yoichi Minami, Guangwei Cui, Takuma Asahi, Ryutaro Ono, Yuh Sasawaki, Eiichi Konishi, Seung-Hee Yoo, Zheng Chen, Satoshi Teramukai, Koichi Ikuta, Kazuhiro Yagita

  Modern society characterized by a 24/7 lifestyle leads to misalignment between environmental cycles and endogenous circadian rhythms. Persisting circadian misalignment leads to deleterious effects on health and healthspan. However, the underlying mechanism remains not fully understood. Here, we subjected adult, wild-type mice to distinct chronic jet-lag paradigms, which showed that long-term circadian misalignment induced significant early mortality. Non-biased RNA sequencing analysis using liver and kidney showed marked activation of gene regulatory pathways associated with the immune system and immune disease in both organs. In accordance, we observed enhanced steatohepatitis with infiltration of inflammatory cells. The investigation of senescence-associated immune cell subsets from the spleens and mesenteric lymph nodes revealed an increase in PD-1+CD44high CD4 T cells as well as CD95+GL7+ germinal center B cells, indicating that the long-term circadian misalignment exacerbates immune senescence and consequent chronic inflammation. Our results underscore immune homeostasis as a pivotal interventional target against clock-related disorders.

  Lead, Feb. 2020, Scientific reports, 10(1) (1), 2569 - 2569, English, International magazine

  [Refereed]

  Scientific journal


• Glucocorticoids Drive Diurnal Oscillations in T Cell Distribution and Responses by Inducing Interleukin-7 Receptor and CXCR4.

  Akihiro Shimba, Guangwei Cui, Shizue Tani-Ichi, Makoto Ogawa, Shinya Abe, Fumie Okazaki, Satsuki Kitano, Hitoshi Miyachi, Hisakata Yamada, Takahiro Hara, Yasunobu Yoshikai, Takashi Nagasawa, Günther Schütz, Koichi Ikuta

  Glucocorticoids are steroid hormones with strong anti-inflammatory and immunosuppressive effects that are produced in a diurnal fashion. Although glucocorticoids have the potential to induce interleukin-7 receptor (IL-7R) expression in T cells, whether they control T cell homeostasis and responses at physiological concentrations remains unclear. We found that glucocorticoid receptor signaling induces IL-7R expression in mouse T cells by binding to an enhancer of the IL-7Rα locus, with a peak at midnight and a trough at midday. This diurnal induction of IL-7R supported the survival of T cells and their redistribution between lymph nodes, spleen, and blood by controlling expression of the chemokine receptor CXCR4. In mice, T cell accumulation in the spleen at night enhanced immune responses against soluble antigens and systemic bacterial infection. Our results reveal the immunoenhancing role of glucocorticoids in adaptive immunity and provide insight into how immune function is regulated by the diurnal rhythm.

  Lead, Feb. 2018, Immunity, 48(2) (2), 286 - 298, English, International magazine

  [Refereed]

  Scientific journal


• Interleukin-7 receptor controls development and maturation of late stages of thymocyte subpopulations

  Shizue Tani-ichi, Akihiro Shimba, Keisuke Wagatsuma, Hitoshi Miyachi, Satsuki Kitano, Kumiko Imai, Takahiro Hara, Koichi Ikuta

  Jan. 2013, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 110(2) (2), 612 - 617, English

  [Refereed]

  Scientific journal

• Pleiotropic Effects of Glucocorticoids on the Immune System in Circadian Rhythm and Stress

  Akihiro Shimba, Aki Ejima, Koichi Ikuta

  Frontiers Media S.A., 08 Oct. 2021, Frontiers in Immunology, 12, English

  Book review


• 肝臓内IL-15産生性微小環境による1型自然リンパ球を介した抗腫瘍免疫の制御

  旭拓真, 榛葉旭恒, 崔広為, 阿部真也, 生田宏一

  2020, 日本分子生物学会年会プログラム・要旨集(Web), 43rd


• Glucocorticoids Drive Circadian Changes in T-Cell Homing and Response via IL-7 Receptor

  Akihiro Shimba, Koichi Ikuta

  May 2017, JOURNAL OF IMMUNOLOGY, 198(1) (1), English

  Summary international conference

• Induction of Th17-mediated inflammation via glucocorticoids under stress

  榛葉旭恒, 生田宏一

  医学のあゆみ, Jul. 2026


• グルココルチコイドによる免疫応答能の概日制御

  榛葉旭恒, 生田宏一

  281(2):159-163, 医学のあゆみ, 2022


• T細胞の維持と免疫応答におけるIL-7受容体の発現制御と機能

  榛葉旭恒, 生田宏一

  74(3):219-225, 臨床免疫・アレルギー科, 2020


• グルココルチコイドによる免疫応答の日内変動制御

  榛葉 旭恒, 生田宏一

  感染炎症免疫, Aug. 2019


• 概日リズムが制御する免疫応答の日内変動と炎症疾患

  榛葉 旭恒, 生田宏一

  実験医学, Feb. 2019


• グルココルチコイドによる正負の免疫制御

  榛葉 旭恒, 生田宏一

  生体の科学, 2019


• グルココルチコイドと免疫概日リズムが制御する生体防御機構

  榛葉 旭恒, 生田 宏一

  医学のあゆみ, Sep. 2018


• グルココルチコイドによる免疫機能の日内変動の制御

  生田 宏一, 榛葉 旭恒

  アンチ・エイジング医学, Aug. 2018

• Stress-induced glucocorticoids promote the differentiation of Th17 cells exacerbating inflammatory diseases.

  Akihiro Shimba, Ikuta Koichi

  第52回日本免疫学会総会・学術集会, Dec. 2024

  Oral presentation


• グルココルチコイドの免疫応答促進作用

  榛葉旭恒

  第28回日本時間生物学会学術大会, Nov. 2021, Japanese

  [Invited]

  Nominated symposium


• ストレスはグルココルチコイドを介してTh17細胞を活性化する

  榛葉旭恒, 生田宏一

  Kyoto T Cell Conference, Oct. 2021


• Control of Immunity by Glucocorticoids

  Akihiro Shimba

  第48回日本免疫学会学術集会, Dec. 2019

  [Invited]

  Nominated symposium


• Glucocorticoids drive diurnal changes in distribution and response of T cells via IL-7R expression

  Shimba Akihiro, Cui Guangwei, Ikuta Koichi

  第46回日本免疫学会総会・学術集会, Dec. 2017, English, Domestic conference

  Oral presentation


• Glucocorticoids drive diurnal changes in distribution and response of T cells via IL-7R expression

  Shimba Akihiro, Ikuta Koichi

  24th East Asia Joint Symposium, Oct. 2017, English, International conference

  Oral presentation


• グルココルチコイドによる IL-7R および CXCR4 の発現を介した T 細胞維持への影響

  榛葉 旭恒, 生田 宏一

  Kyoto T Cell Conference, May 2015, Domestic conference

  Oral presentation


• Differential roles of IL-7 and IL-2 receptor signals in lymphocyte development and maintenance revealed by IL-7Rα/IL-15Rβ chimera knock-in

  Akihiro Shimba, Shizue Tani-Ichi, Kyoko Masuda, Takahiro Hara, Hiroshi Kawamoto, Koichi Ikuta

  第43回日本免疫学会総会・学術集会, Dec. 2014, English, Domestic conference

  Oral presentation

• THE JAPANESE SOCIETY FOR IMMUNOLOGY


• 日本時間生物学会

• リソソーム機能の概日リズムがCD8T細胞の抗がん免疫応答を制御する機構の解明

  榛葉 旭恒

  日本学術振興会, 科学研究費助成事業, 基盤研究(C), 京都大学, Apr. 2025 - Mar. 2028


• がん細胞が免疫細胞の概日リズムの乱れを誘導して抗がん免疫応答を減退させる機構の解明

  公益財団法人持田記念医学薬学振興財団, Jan. 2026 - Dec. 2026, Principal investigator


• Control of immune response and tissue homeostasis by novel IL-15-dependent innate lymphocytes

  生田 宏一, 榛葉 旭恒, 阿部 真也, 谷一 靖江

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (B), Kyoto University, 01 Apr. 2023 - 31 Mar. 2026


• Development of nighttime lighting to promote patient sleep under metameric conditions

  若村 智子, 中本 五鈴, 福田 裕美, 高雄 元晴, 榛葉 旭恒

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Challenging Research (Exploratory), Kyoto University, 30 Jun. 2023 - 31 Mar. 2025


• ストレスがTH17細胞のプロテアーゼの発現上昇と関節炎増悪に寄与する機構の解明

  榛葉 旭恒

  日本学術振興会, 科学研究費助成事業, 基盤研究(C), 京都大学, 01 Apr. 2022 - 31 Mar. 2025


• IL-15-producing microenvironment supporting innate lymphoid cells and its role in diseases

  生田 宏一, 榛葉 旭恒, 谷一 靖江, 崔 广為

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (B), Kyoto University, 01 Apr. 2020 - 31 Mar. 2023

  自然リンパ球、NK細胞、NKT細胞などの自然免疫系リンパ球は、感染免疫応答、抗腫瘍免疫、炎症免疫疾患などにおいて重要な働きをしている。自然免疫系リンパ球の分化・維持・機能にはIL-15が必須であるが、どの細胞が作るIL-15に依存するのかという問題は未解決である。本研究は、独自に作製した細胞特異的IL-15欠損マウスを用いて、NK細胞とNKT細胞の分化・維持・機能を支える骨髄と胸腺のIL-15産生性免疫微小環境を同定し、その感染防御・抗腫瘍免疫・慢性炎症における機能を明らかにする。そのために、Ａ.自然免疫系リンパ球を支える骨髄IL-15産生性微小環境の同定と病態における役割、Ｂ.胸腺IL-15産生性微小環境に依存する新規iNKT細胞の機能と病態における役割、の２つの研究項目について研究を推進した。 骨髄で分化するNK細胞については、NK細胞のレポーターマウス（Ncr1-Cre R26R-tdTomato）を用いて、第１世代Cubic法にて透明化を施した後で免疫染色をおこない、広域で深部にわたる骨髄NK細胞のイメージングに成功し、骨髄内で散在性のNK細胞とクラスターを形成するNK細胞の２種類の集団が存在することを明らかにした。今後は、ケモカインの関与などNK細胞クラスターを形成する機構の解明をおこなう。胸腺で分化するiNKT細胞については、胸腺IL-15欠損マウスにメラノーマ細胞を移入し肺転移巣を解析した結果、転移巣が増加していたことから、新規CD244陽性iNKT細胞が分泌するIFN-gがNK細胞を活性化して、腫瘍細胞の排除に重要な働きをすることを明らかにした。今後は、脂肪組織におけるCD244陽性iNKT細胞の機能を解析するとともに、このCD244陽性iNKT細胞のヒトにおける相同集団を解析し、新規CD244陽性iNKT細胞の免疫系における機能を統一的に理解する。


• Induction of autoimmune diseases by glucocorticoids

  IKUTA Koichi

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Challenging Research (Exploratory), Kyoto University, 30 Jul. 2020 - 31 Mar. 2022

  Glucocorticoids (GC) have immunosuppressive effects and are used for treatment of autoimmune diseases. We demonstrated that oscillating GC promote accumulation of T cells into lymphoid organs and enhance immune responses, thereby demonstrating a new physiological function of GC on the immune system. In this study, we demonstrated that GC promote the differentiation and function of inflammation-inducing Th17 cells and enhance the development of autoimmune diseases, by using T cell- and Th17 cell-specific GR-deficient mice. Thus, we established a novel concept that GC with strong immunosuppressive effects induces autoimmune diseases at physiological concentrations.


• Stress-induced renin causes intestinal inflammation via helper T cells

  Shimba Akihiro

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Early-Career Scientists, Kyoto University, 01 Apr. 2020 - 31 Mar. 2022

  Renin, which controls blood pressure, binds to (pro)renin receptor (PRR). Although hematopoietic cells express PRR, the function of PRR remain unclear. To address this question, we analyzed lymphocyte-specific PRR-deleted mice. We found that T, B, and innate lymphoid cells were significantly reduced in PRR deficient mice. Furthermore, pro-renin enhanced helper T cell differentiation in vitro. Taken together, these results suggest a possibility that the signals of pro-renin receptor promote the development and maintenance of lymphocyte subsets to cause intestinal inflammation.


• グルココルチコイドがTh17細胞の機能を促進し腸管免疫を制御する機構の解明

  榛葉 旭恒

  科学研究費助成事業, 若手研究, Apr. 2018 - Mar. 2020, Principal investigator

  Competitive research funding


• グルココルチコイドによるIL-17産生型ヘルパーＴ細胞の分化・維持と炎症惹起を促進する機能の解明

  榛葉 旭恒

  清水免疫学・神経科学振興財団, 2019


• グルココルチコイドによるIL-17産生型ヘルパーT細胞の分化・維持・免疫応答の促進機能の解明

  榛葉 旭恒

  金原一郎記念医学医療振興財団, 平成30年度上期助成事業, 2018, Principal investigator

  Competitive research funding


• グルココルチコイドによるIL-17産生型ヘルパーT細胞分化・維持・免疫応答の促進機能の解明

  榛葉 旭恒

  一般財団法人藤原記念財団, 奨励金・補助金, 2018, Principal investigator

  Competitive research funding


• グルココルチコイドによる免疫機能と自己免疫疾患の亢進機構

  榛葉 旭恒

  武田科学振興財団, 2019年度 医学系研究助成, 基礎, Principal investigator