title: Follicular T-helper cell recruitment governed by bystander B cells and ICOS-driven motility.
abstract: Germinal centres support antibody affinity maturation and memory formation. Follicular T-helper cells promote proliferation and differentiation of antigen-specific B cells inside the follicle. A genetic deficiency in the inducible co-stimulator (ICOS), a classic CD28 family co-stimulatory molecule highly expressed by follicular T-helper cells, causes profound germinal centre defects, leading to the view that ICOS specifically co-stimulates the follicular T-helper cell differentiation program. Here we show that ICOS directly controls follicular recruitment of activated T-helper cells in mice. This effect is independent from ICOS ligand (ICOSL)-mediated co-stimulation provided by antigen-presenting dendritic cells or cognate B cells, and does not rely on Bcl6-mediated programming as an intermediate step. Instead, it requires ICOSL expression by follicular bystander B cells, which do not present cognate antigen to T-helper cells but collectively form an ICOS-engaging field. Dynamic imaging reveals ICOS engagement drives coordinated pseudopod formation and promotes persistent T-cell migration at the border between the T-cell zone and the B-cell follicle in vivo. When follicular bystander B cells cannot express ICOSL, otherwise competent T-helper cells fail to develop into follicular T-helper cells normally, and fail to promote optimal germinal centre responses. These results demonstrate a co-stimulation-independent function of ICOS, uncover a key role for bystander B cells in promoting the development of follicular T-helper cells, and reveal unsuspected sophistication in dynamic T-cell positioning in vivo.
authors.affiliation: Tsinghua-Peking Center for Life Sciences, Laboratory of Dynamic Immunobiology, School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Heping
authors.initials: H
authors.lastname: Xu
authors.forename: Xuanying
authors.initials: X
authors.lastname: Li
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.forename: Jianfu
authors.initials: J
authors.lastname: Li
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Shiyue
authors.initials: S
authors.lastname: Hou
authors.forename: Lixia
authors.initials: L
authors.lastname: Peng
authors.forename: Chenguang
authors.initials: C
authors.lastname: Xu
authors.forename: Wanli
authors.initials: W
authors.lastname: Liu
authors.forename: Lianfeng
authors.initials: L
authors.lastname: Zhang
authors.forename: Hai
authors.initials: H
authors.lastname: Qi
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D024201:Bystander Effect / Q000276:immunology*; D002465:Cell Movement; D004268:DNA-Binding Proteins / Q000378:metabolism; D005838:Genotype; D018858:Germinal Center / Q000166:cytology* / Q000276:immunology; D060945:Inducible T-Cell Co-Stimulator Ligand / Q000378:metabolism; D060889:Inducible T-Cell Co-Stimulator Protein / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D051560:Proto-Oncogene Proteins c-bcl-6; D011554:Pseudopodia / Q000378:metabolism; D054380:Receptors, CXCR5; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000276:immunology*
chemical_list: C490010:Bcl6 protein, mouse; C513179:CXCR5 protein, mouse; D004268:DNA-Binding Proteins; C400230:Icosl protein, mouse; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D051560:Proto-Oncogene Proteins c-bcl-6; D054380:Receptors, CXCR5