PPubMed19 Jul 2023Cited 31×

IL-21 shapes germinal center polarization via light zone B cell selection and cyclin D3 upregulation IL-21 promotes germinal center polarization

Lina Petersone, Chun Jing Wang, Natalie M. Edner, Astrid Fabri, Spyridoula-Angeliki Nikou, Claudia Hinze, Ellen M. Ross, Elisavet Ntavli, Yassin Elfaki, Frank Heuts, Vitalijs Ovcinnikovs, Andrea Rueda Gonzalez, Luke P. Houghton, Hannah M. Li, Yang Zhang, Kai-Michael Toellner, Lucy S.K. Walker

Abstract

'Spyridoula-Angeliki Nikou' 'Claudia Hinze' 'Ellen M. Ross' 'Elisavet Ntavli' 'Yassin Elfaki' 'Frank Heuts' 'Vitalijs Ovcinnikovs' 'Andrea Rueda Gonzalez' 'Luke P. Houghton' 'Hannah M. Li' 'Yang Zhang' 'Kai-Michael Toellner' 'Lucy S.K. Walker'] Petersone et al. investigate IL-21-dependent germinal center (GC) regulation and reveal key roles for IL-21 in promoting light zone GC B cell selection and controlling dark zone GC B cell proliferation by upregulation of cyclin D3.

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IL-21 drives germinal center polarization by enhancing light‑zone B cell selection and up‑regulating cyclin D3‑driven dark‑zone proliferation.

What’s new

i.Demonstrated that IL-21 promotes light‑zone germinal‑center B cell selection
ii.Showed IL-21 regulates dark‑zone B cell proliferation via cyclin D3 up‑regulation
iii.Identified Foxo1 as a mediator of IL-21‑induced cyclin D3 expression
iv.Provided evidence that IL-21 shapes GC polarization in chronic (CTLA‑4‑/‑) and immunized mouse models
v.Established that IL-21 does not affect GC B cell apoptosis

How they did it

The study used IL‑21R‑deficient and CTLA‑4‑deficient mice, SRBC immunization, flow cytometry, confocal microscopy, in‑vitro B‑cell stimulation with IL‑21 and anti‑CD40, bone‑marrow chimeras, and statistical analysis (Mann‑Whitney, Kruskal‑Wallis, ANOVA).

What they found

IL‑21R deficiency reduced Tfh cell frequencies and absolute numbers (P<0.0001, n=7‑21)
GC B cell frequencies were markedly lower in IL‑21R−/− CTLA‑4−/− mice (P<0.0001)
IL‑21R−/− mice showed a skew toward light‑zone GC B cells after SRBC immunization (n=5‑14, P<0.01)
Caspase activity in GC B cells was comparable between WT and IL‑21R−/− mice (ns)
IL‑21 dose‑dependently increased Foxo1 MFI; inhibition of Foxo1 reduced cyclin D3 up‑regulation (n=4‑7, P<0.001)

Caveats

✕Findings are limited to mouse models and may not translate to humans
✕Only early time points (up to 10 days post‑immunization) were examined
✕Incomplete inhibition of cyclin D3 suggests additional pathways were not identified

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