@article{bffb85789bf744acbdc8f127a9e873be,
title = "Interleukin-21, acting beyond the immunological synapse, independently controls T follicular helper and germinal center B cells",
abstract = "Germinal centers (GCs), transient structures within B cell follicles and central to affinity maturation, require the coordinated behavior of T and B cells. IL-21, a pleiotropic T cell-derived cytokine, is key to GC biology through incompletely understood mechanisms. By genetically restricting production and receipt of IL-21 in vivo, we reveal how its independent actions on T and B cells combine to regulate the GC. IL-21 established the magnitude of the GC B cell response by promoting CD4+ T cell expansion and differentiation in a dose-dependent manner and with paracrine activity. Within GC, IL-21 specifically promoted B cell centroblast identity and, when bioavailability was high, plasma cell differentiation. Critically, these actions may occur irrespective of cognate T-B interactions, making IL-21 a general promoter of growth as distinct to a mediator of affinity-driven selection via synaptic delivery. This promiscuous activity of IL-21 explains the consequences of IL-21 deficiency on antibody-based immunity.",
keywords = "affinity maturation, B cell memory, germinal centers, humoral immunity, interleukin 21, T follicular helper cells",
author = "Isaak Quast and Dvorscek, {Alexandra R.} and Celine Pattaroni and Steiner, {Thiago M.} and McKenzie, {Craig I.} and Catherine Pitt and Kristy O'Donnell and Zhoujie Ding and Hill, {Danika L.} and Robert Brink and Robinson, {Marcus J.} and Dimitra Zotos and Tarlinton, {David M.}",
note = "Funding Information: We thank Lynn M. Corcoran, William R. Heath, Warren J. Leonard, and Stephen L. Nutt for mouse strains; Axel Kallies, Benjamin Marsland, and Roxanne Chatzis for help with RNA-seq; the Alfred Alliance Monash Intensive Care Unit and Monash Animal Research Platform staff for animal husbandry; and Stephanie Jansen for experimental assistance. The authors acknowledge Stephen Cody and Irena Carmichael (Monash Micro Imaging); Ali Shad (Monash Histology Platform); M{\'e}lanie Le Page (Alfred Research Alliance FlowCore); Eva Orlowski and Magdaline Costa (AMREPFlow); Noelene Quinsey (Monash Protein Production Unit); Tim Adams, Tam Pham, Tram Phan, and George Lovercz (Commonwealth Scientific and Industrial Research Organisation, CSIRO). D.M.T. was funded by an Investigator Award ( 1175411 ) provided by the National Health and Medical Research Council (NHMRC) of Australia, I.Q. by an Early (P2ZHP3_164964) and an Advanced Postdoc Mobility fellowship ( P300PA_177893 ) provided by the Swiss National Science Foundation and a Peter Doherty fellowship ( 1145136 ) provided by NHMRC Australia, A.R.D. by a Monash University Research Training Program Stipend, and Z.D. by a Swedish International Postdoctoral Fellowship ( 2016–06659 ) provided by the Swedish Institute for Health Sciences (V{\aa}rdalinstitutet). This work was supported by NHMRC Project Grant 1146617 awarded to D.M.T., D.Z., and I.Q.; NHMRC Ideas Grants 1185294 awarded to M.J.R. and I.Q. and 2002393 awarded to I.Q.; and Monash Platform Access grant PAG18-0409 awarded to I.Q. and D.Z. Funding Information: We thank Lynn M. Corcoran, William R. Heath, Warren J. Leonard, and Stephen L. Nutt for mouse strains; Axel Kallies, Benjamin Marsland, and Roxanne Chatzis for help with RNA-seq; the Alfred Alliance Monash Intensive Care Unit and Monash Animal Research Platform staff for animal husbandry; and Stephanie Jansen for experimental assistance. The authors acknowledge Stephen Cody and Irena Carmichael (Monash Micro Imaging); Ali Shad (Monash Histology Platform); M{\'e}lanie Le Page (Alfred Research Alliance FlowCore); Eva Orlowski and Magdaline Costa (AMREPFlow); Noelene Quinsey (Monash Protein Production Unit); Tim Adams, Tam Pham, Tram Phan, and George Lovercz (Commonwealth Scientific and Industrial Research Organisation, CSIRO). D.M.T. was funded by an Investigator Award (1175411) provided by the National Health and Medical Research Council (NHMRC) of Australia, I.Q. by an Early (P2ZHP3_164964) and an Advanced Postdoc Mobility fellowship (P300PA_177893) provided by the Swiss National Science Foundation and a Peter Doherty fellowship (1145136) provided by NHMRC Australia, A.R.D. by a Monash University Research Training Program Stipend, and Z.D. by a Swedish International Postdoctoral Fellowship (2016–06659) provided by the Swedish Institute for Health Sciences (V{\aa}rdalinstitutet). This work was supported by NHMRC Project Grant 1146617 awarded to D.M.T. D.Z. and I.Q.; NHMRC Ideas Grants 1185294 awarded to M.J.R. and I.Q. and 2002393 awarded to I.Q.; and Monash Platform Access grant PAG18-0409 awarded to I.Q. and D.Z. Conceptualization, I.Q. and D.M.T.; Methodology, I.Q. C. Pattaroni, T.M.S. D.L.H. Z.D. K.O.D. R.B. M.J.R. and D.Z.; Investigation, I.Q. A.R.D. C. Pattaroni, C.I.M. C. Pitt, and K.O.D.; Writing - original draft, I.Q. and D.M.T.; Writing - review and editing, I.Q. A.R.D. C. Pattaroni, T.M.S. C.I.M. D.L.H. Z.D. C. Pitt, K.O.D. R.B. M.J.R. D.Z. and D.M.T. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",
year = "2022",
month = aug,
day = "9",
doi = "10.1016/j.immuni.2022.06.020",
language = "English",
volume = "55",
pages = "1414--1430.e5",
journal = "Immunity",
issn = "1074-7613",
publisher = "Elsevier",
number = "8",
}