title: T-B-cell entanglement and ICOSL-driven feed-forward regulation of germinal centre reaction.
abstract: The germinal centre (GC) reaction supports affinity-based B-cell competition and generates high-affinity bone-marrow plasma cells (BMPCs). How follicular T-helper (TFH) cells regulate GC selection is not clear. Using competitive mixed chimaera, we show here that, beyond the role in promoting TFH development, ICOSL (inducible T-cell co-stimulator ligand, also known as ICOSLG) is important for individual B cells to competitively participate in the GC reaction and to develop into BMPCs. Using intravital imaging aided by a calcium reporter, we further show that ICOSL promotes an 'entangled' mode of TFH-B-cell interactions, characterized by brief but extensive surface engagement, productive T-cell calcium spikes, and B-cell acquisition of CD40 signals. Reiterated entanglement promotes outer-zone co-localization of outcompeting GC B cells together with TFH cells, affording the former increased access to T-cell help. ICOSL on GC B cells is upregulated by CD40 signals. Such an intercellular positive feedback between contact-dependent help and ICOSL-controlled entanglement promotes positive selection and BMPC development, as evidenced by observations that higher-affinity B-cell receptor variants are enriched in the ICOSL(high) fraction, that numerically disadvantaged ICOSL-deficient GC B cells or BMPCs exhibit strong affinity compensation in competitive chimaera, and that when GC competition proceeds without ICOSL, selection of high-affinity variants in otherwise normal GC reactions is impaired. By demonstrating entanglement as the basic form of GC TFH-B-cell interactions, identifying ICOSL as a molecular linkage between T-B interactional dynamics and positive selection for high-affinity BMPC formation, our study reveals a pathway by which TFH cells control the quality of long-lived humoral immunity.
authors.affiliation: Tsinghua-Peking Center for Life Sciences, Laboratory of Dynamic Immunobiology, School of Medicine, Tsinghua University, 100084 Beijing, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.affiliation: Tsinghua-Peking Center for Life Sciences, Laboratory of Dynamic Immunobiology, School of Medicine, Tsinghua University, 100084 Beijing, China.
authors.forename: Heping
authors.initials: H
authors.lastname: Xu
authors.affiliation: Tsinghua-Peking Center for Life Sciences, Laboratory of Dynamic Immunobiology, School of Medicine, Tsinghua University, 100084 Beijing, China.
authors.forename: Changming
authors.initials: C
authors.lastname: Shih
authors.affiliation: Tsinghua-Peking Center for Life Sciences, Laboratory of Dynamic Immunobiology, School of Medicine, Tsinghua University, 100084 Beijing, China.
authors.forename: Zurong
authors.initials: Z
authors.lastname: Wan
authors.affiliation: School of Life Sciences, Tsinghua University, 100084 Beijing, China.
authors.forename: Xiaopeng
authors.initials: X
authors.lastname: Ma
authors.affiliation: Tsinghua-Peking Center for Life Sciences, Laboratory of Dynamic Immunobiology, School of Medicine, Tsinghua University, 100084 Beijing, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Ma
authors.affiliation: Tsinghua-Peking Center for Life Sciences, Laboratory of Dynamic Immunobiology, School of Medicine, Tsinghua University, 100084 Beijing, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Luo
authors.affiliation: Tsinghua-Peking Center for Life Sciences, Laboratory of Dynamic Immunobiology, School of Medicine, Tsinghua University, 100084 Beijing, China.
authors.forename: Hai
authors.initials: H
authors.lastname: Qi
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000378:metabolism; D000917:Antibody Formation; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D005246:Feedback; D018858:Germinal Center / Q000166:cytology* / Q000276:immunology*; D060945:Inducible T-Cell Co-Stimulator Ligand / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D010950:Plasma Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism
chemical_list: D000906:Antibodies; C400230:Icosl protein, mouse; D060945:Inducible T-Cell Co-Stimulator Ligand