Anti-Tumor Therapy, Autoimmunity, B Cells, Cellular Differentiation, Cellular Immunity, Cytokines, Dendritic Cells, Immunology, Infectious Disease, Inflammation, Influenza Virus, Lupus Nephritis, Lymphocytes, Macrophage, Molecular Biology, Signal Transduction, Systems Biology, T Cells
Multi-Disciplinary Training Areas
Clinical Research Education Program [CLR], Immunology [IMM], Microbiology [MIC]
MD, Kyoto University
PhD, Graduate School of Medicine, Kyoto University
Post-doctoral fellow, Baylor Institute for Immunology Research
Human TFH cell subsets and their roles in diseases/vaccinations
His lab has shown that CXCR5+ memory CD4+ T cells in human blood likely represent the circulating memory compartment of TFH cells. They further demonstrated that these circulating TFH cells (cTFH cells) are composed of three major subsets which share properties with TH1, TH2, and TH17 cells, and these subsets display different abilities to help B cells. They also provided evidence that the alteration in the composition of these subsets is associated with the pathogenesis of human autoimmune diseases. These findings were largely confirmed by studies performed by other laboratories and in many human autoimmune diseases. By using human tonsil samples, his lab has also demonstrated that TFH cells within germinal centers and TFH-lineage cells outside germinal centers display distinct gene expression profiles and functions. These studies have lead to their identification of a major TFH subset associated with the generation of antibody responses after influenza vaccines in humans. • Morita R,…., Ueno H. Immunity. 2011;34(1):108-21. • Bentebibel S-E,.., Ueno H. Proc Natl Acad Sci U S A. 2011;10.1073/pnas.1100898108. • Bentebibel SE#, Lopez S#, Obermoser G#, Schmitt N#,……, Ramilo O*, Ueno H*. Sci Transl Med. 2013;5(176):176ra32.
Phenotypic and functional characterization of human dendritic cell subsets
His lab has shown that human skin dendritic cell subsets are functionally distinct and play distinct roles in the generation of immune responses. These studies also provided insights into the designs of dendritic cell-based immunotherapies for various diseases. • Cao T*, Ueno H* et al. Eur J Immunol. 2007;37(9):2657-67. • Klechevsky E#, Morita R#,...Ueno H. Immunity. 2008;29(3):497-510.
Comprehensive analysis of antigen-specific T cell repertoires in human blood
He has developed a novel assay which permits a comprehensive analysis of antigen-specific T cell repertoires in human blood (EpiMax). By using EpiMax together with other immunomonitoring tools, his lab has analyzed antigen-specific T cell subsets in patients with different diseases, and published findings including that 1) Patients with metastatic melanoma display tumor antigen-specific IL-10-producing regulatory T cells in blood. 2) Vaccinations with dendritic cells loaded with killed tumor cells induce a broad repertoire of tumor-antigen-specific CD8+ and CD4+ T cells in patients with metastatic melanoma. 3) Type 1 diabetes children and type 1 diabetes adults display distinct sets of islet antigen-specific CD4+ T cells. • Palucka AK*, Ueno H*, et al. J Immunother. 2006;29(5):545-57. • Vence L,…., Ueno H. Proc Natl Acad Sci U S A. 2007;104(52):20884-9. • Chujo D,……., Ueno H. Clin Immunol. 2015;161(2):270-7
Identification of developmental pathways of human T follicular helper (TFH) cells
His lab has discovered multiple mechanisms that promote the differentiation of TFH cells in humans. They initially demonstrated that IL-12 induces human naïve CD4+ T cells to become IL-21+ TFH-like cells. Later, they have shown that children deficient of IL-12 receptor (beta 1 chain) show decreased circulating TFH cells and memory B cells in blood, and an altered formation of germinal centers in lymph nodes, indicating the importance of signals mediated via IL-12 receptor (thus IL-12 and IL-23) for optimal TFH response in vivo in humans. His recent study further identified that TGF-beta acts together with IL-12 and IL-23 to drive the differentiation of human naïve CD4+ T cells towards the TFH lineage. Interestingly, this pathway is shared with TH17 cell differentiation in humans. Given that both TFH and TH17 cell responses are often excessive in autoimmune disease patients, this pathway is likely involved in the co-development of the two T cell lineages in these diseases. His most recent study demonstrated that signals through Ox40 also promote the differentiation of TFH cells in humans, and provided evidence that the OX40-Ox40 ligand axis is involved in the generation of aberrant TFH response in systemic lupus erythematosus patients. • Schmitt N,…, Ueno H. Immunity. 2009;31(1):158-69. • Schmitt N,…, Ueno H. Blood. 2013;121(17):3375-85. • Schmitt N,…, Ueno H. Nat Immunol. 2014;15(9):856-65. • Jacquemin C#, Schmitt N#, Contin-Bordes C#,…., Ueno H*, Blanco P*. Immunity. 2015;42(6):1159-70.
Palucka* AK, Ueno* H, Connolly J, Kerneis-Norvell F, Blanck JP, Johnston DA, Fay* J, Banchereau* J. Dendritic cells loaded with killed allogeneic melanoma cells can induce objective clinical responses and MART-1 specific CD8+ T-cell immunity. J Immunother 2006; 29.
Vence L, Palucka AK, Fay JW, Ito T, Liu YJ, Banchereau J, Ueno H. Circulating tumor antigen-specific regulatory T cells in patients with metastatic melanoma. PNAS 2007 Dec; 104(52).
Cao* T, Ueno* H, Glaser C, Fay JW, Palucka AK, Banchereau J. Both Langerhans cells and interstitial DC cross-present melanoma antigens and efficiently activate antigen-specific CTL. Eur J Immunol 2007 Sep; 37(9).
Klechevsky E, Morita R, Liu M, Cao Y, Coquery S, Thompson-Snipes L, Briere F, Chaussabel D, Zurawski G, Palucka AK, Reiter Y, Banchereau J, Ueno H. Functional specializations of human epidermal Langerhans cells and CD14+ dermal dendritic cells. Immunity 2008 Sep; 29(3).
Dullaers M, Li D, Xue Y, Ni L, Gayet I, Morita R, Ueno H, Palucka KA, Banchereau J, Oh S. A T cell-dependent mechanism for the induction of human mucosal homing immunoglobulin A-secreting plasmablasts. Immunity 2009 Jan; 30(1).
Schmitt N, Morita R, Bourdery L, Bentebibel SE, Zurawski SM, Banchereau J, Ueno H. Human dendritic cells induce the differentiation of interleukin-21-producing T follicular helper-like cells through interleukin-12. Immunity 2009 Jul; 31(1).
Ueno H, Schmitt N, Klechevsky E, Pedroza-Gonzalez A, Matsui T, Zurawski G, Oh S, Fay J, Pascual V, Banchereau J, Palucka K. Harnessing human dendritic cell subsets for medicine. Immunol Rev 2010 Mar; 234(1).
Ueno H, Palucka AK, Banchereau J. The expanding family of dendritic cell subsets. Nat Biotech 2010 Aug; 28(8).
Bentebibel SE, Schmitt N, Banchereau J, Ueno H. Human tonsil B-cell lymphoma 6 (BCL6)-expressing CD4+ T-cell subset specialized for B-cell help outside germinal centers. PNAS 2011 Aug; 108(33).
Morita R, Schmitt N, Bentebibel SE, Ranganathan R, Bourdery L, Zurawski G, Foucat E, Dullaers M, Oh S, Sabzghabaei N, Lavecchio EM, Punaro M, Pascual V, Banchereau J, Ueno H. Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity 2011 Jan; 34(1).
Ueno H, Klechevsky E, Schmitt N, Ni L, Flamar AL, Zurawski S, Zurawski G, Palucka K, Banchereau J, Oh S. Targeting human dendritic cell subsets for improved vaccines. Semin Immunol 2011 Feb; 23(1).
Schmitt N, Bustamante J, Bourdery L, Bentebibel SE, Boisson-Dupuis S, Hamlin F, Tran MV, Blankenship D, Pascual V, Savino DA, Banchereau J, Casanova JL, Ueno H. IL-12 receptor β1 deficiency alters in vivo T follicular helper cell response in humans. Blood 2013 Apr; 121(17).
Obermoser G, Presnell S, Domico K, Xu H, Wang Y, Anguiano E, Thompson-Snipes L, Ranganathan R, Zeitner B, Bjork A, Anderson D, Speake C, Ruchaud E, Skinner J, Alsina L, Sharma M, Dutartre H, Cepika A, Israelsson E, Nguyen P, Nguyen QA, Harrod AC, Pascual V, Ueno H, Nepom GT, Quinn C, Blankenship D, Palucka K, Banchereau J, Chaussabel D. Systems scale interactive exploration reveals quantitative and qualitative differences in response to influenza and pneumococcal vaccines. Immunity 2013 Apr; 38(4).
Bentebibel SE, Lopez S, Obermoser G, Schmitt N, Mueller C, Harrod C, Flano E, Mejias A, Albrecht RA, Blankenship D, Xu H, Pascual V, Banchereau J, Garcia-Sastre A, Palucka AK, Ramilo O, Ueno H. Induction of ICOS+CXCR3+CXCR5+ TH cells correlates with antibody responses to influenza vaccination. Sci Transl Med 2013 Mar; 5(176).
Schmitt N, Ueno H. Blood Tfh cells come with colors. Immunity 2013 Oct; 39(4).
Schmitt N, Liu Y, Bentebibel SE, Munagala I, Bourdery L, Venuprasad K, Banchereau J, Ueno H. The cytokine TGF-β co-opts signaling via STAT3-STAT4 to promote the differentiation of human TFH cells. Nat Immunol 2014 Sep; 15(9).
Schmitt N, Bentebibel SE, Ueno H. Phenotype and functions of memory Tfh cells in human blood. Trends Immunol 2014 Sep; 35(9).
Schmitt N, Ueno H. Regulation of human helper T cell subset differentiation by cytokines. Curr Opin Immunol 2015 Jun; 34.
Ueno H, Banchereau J, Vinuesa CG. Pathophysiology of T follicular helper cells in humans and mice. Nat Immunol 2015 Feb; 16(2).
Jacquemin C, Schmitt N, Contin-Bordes C, Liu Y, Narayanan P, Seneschal J, Maurouard T, Dougall D, Davizon ES, Dumortier H, Douchet I, Raffray L, Richez C, Lazaro E, Duffau P, Truchetet ME, Khoryati L, Mercié P, Couzi L, Merville P, Schaeverbeke T, Viallard JF, Pellegrin JL, Moreau JF, Muller S, Zurawski S, Coffman RL, Pascual V, Ueno* H, Blanco* P. OX40 Ligand Contributes to Human Lupus Pathogenesis by Promoting T Follicular Helper Response. Immunity 2015 Jun; 42(6).
Kathania M, Khare P, Zeng M, Cantarel B, Zhang H, Ueno H, Venuprasad K. Itch inhibits IL-17-mediated colon inflammation and tumorigenesis by ROR-γt ubiquitination. Nat Immunol 2016 Jun;.
Schmitt N, Liu Y, Bentebibel SE, Ueno H. Molecular Mechanisms Regulating T Helper 1 versus T Follicular Helper Cell Differentiation in Humans. Cell Rep;.
Bentebibel SE, Khurana S, Schmitt N, Kurup P, Mueller C, Obermoser G, Palucka AK, Albrecht RA, Garcia-Sastre A, Golding H, Ueno H. ICOS(+)PD-1(+)CXCR3(+) T follicular helper cells contribute to the generation of high-avidity antibodies following influenza vaccination. Scientific reports 2016; 6.
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