title: Crucial roles of interleukin-7 in the development of T follicular helper cells and in the induction of humoral immunity.
abstract: T follicular helper (Tfh) cells are specialized providers of cognate B cell help, which is important in promoting the induction of high-affinity antibody production in germinal centers (GCs). Interleukin-6 (IL-6) and IL-21 have been known to play important roles in Tfh cell differentiation. Here, we demonstrate that IL-7 plays a pivotal role in Tfh generation and GC formation in vivo, as treatment with anti-IL-7 neutralizing antibody markedly impaired the development of Tfh cells and IgG responses. Moreover, codelivery of mouse Fc-fused IL-7 (IL-7-mFc) with a vaccine enhanced the generation of GC B cells as well as Tfh cells but not other lineages of T helper cells, including Th1, Th2, and Th17 cells. Interestingly, a 6-fold-lower dose of an influenza virus vaccine codelivered with Fc-fused IL-7 induced higher antigen-specific and cross-reactive IgG titers than the vaccine alone in both mice and monkeys and led to markedly enhanced protection against heterologous influenza virus challenge in mice. Enhanced generation of Tfh cells by IL-7-mFc treatment was not significantly affected by the neutralization of IL-6 and IL-21, indicating an independent role of IL-7 on Tfh differentiation. Thus, IL-7 holds promise as a critical cytokine for selectively inducing Tfh cell generation and enhancing protective IgG responses.
  
  
  OBJECTIVE
  Here, we demonstrate for the first time that codelivery of Fc-fused IL-7 significantly increased influenza virus vaccine-induced antibody responses, accompanied by robust expansion of Tfh cells and GC B cells as well as enhanced GC formation. Furthermore, IL-7-mFc induced earlier and cross-reactive IgG responses, leading to striking protection against heterologous influenza virus challenge. These results suggest that Fc-fused IL-7 could be used for inducing strong and cross-protective humoral immunity against highly mutable viruses, such as HIV and hepatitis C virus, as well as influenza viruses.
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Gyungbuk, Republic of Korea.
authors.forename: Yong Bok
authors.initials: YB
authors.lastname: Seo
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Gyungbuk, Republic of Korea.
authors.forename: Se Jin
authors.initials: SJ
authors.lastname: Im
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Gyungbuk, Republic of Korea.
authors.forename: Hong
authors.initials: H
authors.lastname: Namkoong
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Gyungbuk, Republic of Korea.
authors.forename: Sae Won
authors.initials: SW
authors.lastname: Kim
authors.affiliation: Intergrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Gyungbuk, Republic of Korea.
authors.forename: Young Woo
authors.initials: YW
authors.lastname: Choi
authors.affiliation: Intergrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Gyungbuk, Republic of Korea.
authors.forename: Moon Cheol
authors.initials: MC
authors.lastname: Kang
authors.affiliation: Research Institute, Genexine Co. Ltd., Seongnam, Republic of Korea.
authors.forename: Hye Seong
authors.initials: HS
authors.lastname: Lim
authors.affiliation: Research Institute, Genexine Co. Ltd., Seongnam, Republic of Korea.
authors.forename: Hyun Tak
authors.initials: HT
authors.lastname: Jin
authors.affiliation: Research Institute, Genexine Co. Ltd., Seongnam, Republic of Korea.
authors.forename: Se Hwan
authors.initials: SH
authors.lastname: Yang
authors.affiliation: Rheumatism Research Center, Catholic Institutes of Medical Science, Seoul, Republic of Korea.
authors.forename: Mi La
authors.initials: ML
authors.lastname: Cho
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Gyungbuk, Republic of Korea Intergrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Gyungbuk, Republic of Korea.
authors.forename: You-Me
authors.initials: YM
authors.lastname: Kim
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Gyungbuk, Republic of Korea Intergrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Gyungbuk, Republic of Korea.
authors.forename: Seung-Woo
authors.initials: SW
authors.lastname: Lee
authors.affiliation: College of Medicine and Medical Research Institute, Chungbuk National University, Cheongju, Republic of Korea.
authors.forename: Young Ki
authors.initials: YK
authors.lastname: Choi
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Gyungbuk, Republic of Korea Intergrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Gyungbuk, Republic of Korea.
authors.forename: Charles D
authors.initials: CD
authors.lastname: Surh
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Gyungbuk, Republic of Korea Intergrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Gyungbuk, Republic of Korea Research Institute, Genexine Co. Ltd., Seongnam, Republic of Korea ycsung@postech.ac.kr.
authors.forename: Young Chul
authors.initials: YC
authors.lastname: Sung
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D000917:Antibody Formation / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D005260:Female; D018858:Germinal Center / Q000276:immunology; D000882:Haplorhini / Q000276:immunology; D056724:Immunity, Humoral / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology; D007252:Influenza Vaccines / Q000276:immunology; D015851:Interleukin-7 / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009975:Orthomyxoviridae / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; D007074:Immunoglobulin G; D007252:Influenza Vaccines; D015851:Interleukin-7; C576410:interleukin-7, mouse