Somatic mutations and affinity maturation are impaired by excessive numbers of T follicular helper cells and restored by Treg cells or memory T cells

European Journal of Immunology
Silvia PreiteFederica Sallusto

Abstract

We previously reported that Cd3e-deficient mice adoptively transferred with CD4(+) T cells generate high numbers of T follicular helper (Tfh) cells, which go on to induce a strong B-cell and germinal center (GC) reaction. Here, we show that in this system, GC B cells display an altered distribution between the dark and light zones, and express low levels of activation-induced cytidine deaminase. Furthermore, GC B cells from Cd3e(-/-) mice accumulate fewer somatic mutations as compared with GC B cells from wild-type mice, and exhibit impaired affinity maturation and reduced differentiation into long-lived plasma cells. Reconstitution of Cd3e(-/-) mice with regulatory T (Treg) cells restored Tfh-cell numbers, GC B-cell numbers and B-cell distribution within dark and light zones, and the rate of antibody somatic mutations. Tfh-cell numbers and GC B-cell numbers and dynamics were also restored by pre-reconstitution of Cd3e(-/-) mice with Cxcr5(-/-) Treg cells or non-regulatory, memory CD4(+) T cells. Taken together, these findings underline the importance of a quantitatively regulated Tfh-cell response for an efficient and long-lasting serological response.

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Citations

Apr 26, 2016·European Journal of Immunology·Mayan Amiezer, Tri Giang Phan
May 12, 2016·Annual Review of Immunology·Federica Sallusto
Dec 17, 2017·The Journal of Experimental Medicine·Jared SilverDuane R Wesemann
Dec 16, 2016·The Journal of Biological Chemistry·Robert K AbbottMichail Sitkovsky
Jan 14, 2017·Frontiers in Immunology·Brodie MilesElizabeth Connick
Jun 12, 2018·Frontiers in Immunology·Ute Greczmiel, Annette Oxenius
Jun 21, 2018·Viruses·Julia Niessl, Daniel E Kaufmann
Jan 9, 2019·Frontiers in Immunology·Jiyeon YangMustafa Akkoyunlu
May 1, 2018·Frontiers in Immunology·Adam J KleinmanCristian Apetrei
Dec 14, 2018·Frontiers in Immunology·Brodie Miles, Elizabeth Connick
Aug 14, 2019·Immunological Reviews·Silvia PreitePamela L Schwartzberg
Jul 16, 2021·Nature·Tadashi TakeuchiHiroshi Ohno

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Methods Mentioned

BETA
flow cytometry
ELISA
transgenic
PCR

Software Mentioned

BASELINe
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Prism
GraphPad
FlowJo
QUEST
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ExPASy
Photoshop
OpenLab

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