Follicular T-helper cell recruitment governed by bystander B cells and ICOS-driven motility

• Published in: Nature (London) Vol. 496; no. 7446; pp. 523 - 527
• Main Authors: Xu, Heping, Li, Xuanying, Liu, Dan, Li, Jianfu, Zhang, Xu, Chen, Xin, Hou, Shiyue, Peng, Lixia, Xu, Chenguang, Liu, Wanli, Zhang, Lianfeng, Qi, Hai
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 25.04.2013
• Subjects: Animals; B cells; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Bystander Effect - immunology; Cell Movement; DNA-Binding Proteins - metabolism; Genetic aspects; Genotype; Germinal Center - cytology; Germinal Center - immunology; Immune system; Immunization; Immunology; Inducible T-Cell Co-Stimulator Ligand - metabolism; Inducible T-Cell Co-Stimulator Protein - metabolism; Lymphocyte Activation; Lymphocytes; Mice; Motility; Physiological aspects; Proteins; Proto-Oncogene Proteins c-bcl-6; Pseudopodia - metabolism; Receptors, CXCR5; Recruitment; T cell receptors; T cells; T-Lymphocytes, Helper-Inducer - cytology; T-Lymphocytes, Helper-Inducer - immunology; United States
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature12058

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.