Somatic mutations and affinity maturation are impaired by excessive numbers of T follicular helper cells and restored by Treg cells or memory T cells.
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.
Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland.
Silvia
S
Preite
Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland.
Dirk
D
Baumjohann
Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland.
Mathilde
M
Foglierini
Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland.
Camilla
C
Basso
Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland.
Francesca
F
Ronchi
Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland.
Blanca M
BM
Fernandez Rodriguez
Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland.
Davide
D
Corti
Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland.|Institute of Microbiology, ETH Zürich, Zurich, Switzerland.
Antonio
A
Lanzavecchia
Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland.
Federica
F
Sallusto
D019264:Adoptive Transfer; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D005434:Flow Cytometry; D018858:Germinal Center / Q000276:immunology; D007156:Immunologic Memory / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D060888:Real-Time Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D017252:CD3 Complex; C485468:Cd3e protein, mouse
Antibodies; Germinal center; Lymphopenia; Somatic hypermutation; Tfh cell