Hideki Ueno M.D.

Gensous, N., N. Schmitt, C. Richez, H. Ueno and P. Blanco (2016). “T follicular helper cells, interleukin-21 and systemic lupus erythematosus.” Rheumatology (Oxford): 2016 Aug [Epub ahead of print].

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SLE is a chronic systemic autoimmune disease characterized by a breakdown of tolerance to nuclear antigens and generation of high-affinity pathogenic autoantibodies. These autoantibodies form, with autoantigens, immune complexes that are involved in organ and tissue damages. Understanding how the production of these pathogenic autoantibodies arises is of prime importance. T follicular helper cells (Tfh) and IL-21 have emerged as central players in this process. This article reviews the pathogenic role of Tfh cells and IL-21 in SLE.

Kathania, M., P. Khare, M. Zeng, B. Cantarel, H. Zhang, H. Ueno and K. Venuprasad (2016). “Itch inhibits il-17-mediated colon inflammation and tumorigenesis by ror-gammat ubiquitination.” Nat Immunol: 2016 Jun [Epub ahead of print].

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Dysregulated expression of interleukin 17 (IL-17) in the colonic mucosa is associated with colonic inflammation and cancer. However, the cell-intrinsic molecular mechanisms by which IL-17 expression is regulated remain unclear. We found that deficiency in the ubiquitin ligase Itch led to spontaneous colitis and increased susceptibility to colon cancer. Itch deficiency in the TH17 subset of helper T cells, innate lymphoid cells and gammadelta T cells resulted in the production of elevated amounts of IL-17 in the colonic mucosa. Mechanistically, Itch bound to the transcription factor ROR-gammat and targeted ROR-gammat for ubiquitination. Inhibition or genetic inactivation of ROR-gammat attenuated IL-17 expression and reduced spontaneous colonic inflammation in Itch-/- mice. Thus, we have identified a previously unknown role for Itch in regulating IL-17-mediated colonic inflammation and carcinogenesis.

Bentebibel, S. E., S. Khurana, N. Schmitt, P. Kurup, C. Mueller, G. Obermoser, A. K. Palucka, R. A. Albrecht, A. Garcia-Sastre, H. Golding and H. Ueno (2016). “Icos(+)pd-1(+)cxcr3(+) t follicular helper cells contribute to the generation of high-avidity antibodies following influenza vaccination.” Sci Rep 6: 26494.

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The immune mechanism leading to the generation of protective antibody responses following influenza trivalent inactivated vaccine (TIV) vaccinations remains largely uncharacterized. We recently reported that TIV vaccination induced a transient increase of circulating ICOS(+)PD-1(+)CXCR3(+) T follicular helper (cTfh) cells in blood, which positively correlated with the induction of protective antibody responses measured at day 28. However, whether and how these T cells directly contribute to antibody response remains unclear. In this study, we analyzed the changes after TIV vaccination in the amount and the avidity of the polyclonal antibodies specific for the HA1 subunit of the pandemic H1N1 virus, and analyzed the correlation with the increase of ICOS(+)PD-1(+)CXCR3(+) cTfh cells. We found that both the amount and the avidity of specific antibodies rapidly increased during the first 7 days after TIV. Importantly, the increase of ICOS(+)PD-1(+)CXCR3(+) cTfh cells strongly correlated with the increase in the avidity of antibodies, particularly in subjects who did not have high affinity antibodies at baseline. We propose that ICOS(+)PD-1(+)CXCR3(+) Tfh cells directly contribute to the generation of high-avidity antibodies after TIV vaccinations by selectively interacting with high affinity B cells at extrafollicular sites.

Bentebibel, S. E., S. Khurana, N. Schmitt, P. Kurup, C. Mueller, G. Obermoser, A. K. Palucka, R. A. Albrecht, A. Garcia-Sastre, H. Golding and H. Ueno (2016). “Icos(+)pd-1(+)cxcr3(+) t follicular helper cells contribute to the generation of high-avidity antibodies following influenza vaccination.” Sci Rep 6: 26494.

Full text of this article.

The immune mechanism leading to the generation of protective antibody responses following influenza trivalent inactivated vaccine (TIV) vaccinations remains largely uncharacterized. We recently reported that TIV vaccination induced a transient increase of circulating ICOS(+)PD-1(+)CXCR3(+) T follicular helper (cTfh) cells in blood, which positively correlated with the induction of protective antibody responses measured at day 28. However, whether and how these T cells directly contribute to antibody response remains unclear. In this study, we analyzed the changes after TIV vaccination in the amount and the avidity of the polyclonal antibodies specific for the HA1 subunit of the pandemic H1N1 virus, and analyzed the correlation with the increase of ICOS(+)PD-1(+)CXCR3(+) cTfh cells. We found that both the amount and the avidity of specific antibodies rapidly increased during the first 7 days after TIV. Importantly, the increase of ICOS(+)PD-1(+)CXCR3(+) cTfh cells strongly correlated with the increase in the avidity of antibodies, particularly in subjects who did not have high affinity antibodies at baseline. We propose that ICOS(+)PD-1(+)CXCR3(+) Tfh cells directly contribute to the generation of high-avidity antibodies after TIV vaccinations by selectively interacting with high affinity B cells at extrafollicular sites.

Ueno, H. (2016). “Human Circulating T Follicular Helper Cell Subsets in Health and Disease. ” J Clin Immunol. Mar 17. [Epub ahead of print]

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T follicular helper (Tfh) cells are specialized to provide help to B cells and to induce durable antibody response. Our knowledge on the biology of Tfh cells and their contribution to disease has significantly increased in the past decade. In particular, recent discoveries of functionally distinct subsets within circulating Tfh (cTfh) cells in human blood have provided clues to assess the ongoing Tfh responses in healthy subjects after vaccinations and in patients with autoimmune diseases. The immune pathways associated with Tfh cell differentiation in humans are also getting revealed. In this review, I will first summarize the subsets within human cTfh cells, and discuss their alterations in patients with autoimmune diseases. Then I will discuss the mechanisms associated with the aberrant Tfh responses in human autoimmune diseases.