Follicular regulatory T cells produce neuritin to regulate B cells

Paula Gonzalez-Figueroa; Jonathan A Roco; Ilenia Papa; Lorena Núñez Villacís; Maurice Stanley; Michelle A Linterman; Alexander Dent; Pablo F Canete; Carola G Vinuesa

doi:10.1016/j.cell.2021.02.027

Follicular regulatory T cells produce neuritin to regulate B cells

Cell. 2021 Apr 1;184(7):1775-1789.e19. doi: 10.1016/j.cell.2021.02.027. Epub 2021 Mar 11.

Authors

Paula Gonzalez-Figueroa¹, Jonathan A Roco¹, Ilenia Papa¹, Lorena Núñez Villacís², Maurice Stanley¹, Michelle A Linterman³, Alexander Dent⁴, Pablo F Canete¹, Carola G Vinuesa⁵

Affiliations

¹ Dept of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
² Dept of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
³ Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, UK.
⁴ Dept of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
⁵ Dept of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia. Electronic address: [email protected].

PMID: 33711260
DOI: 10.1016/j.cell.2021.02.027

Abstract

Regulatory T cells prevent the emergence of autoantibodies and excessive IgE, but the precise mechanisms are unclear. Here, we show that BCL6-expressing Tregs, known as follicular regulatory T (Tfr) cells, produce abundant neuritin protein that targets B cells. Mice lacking Tfr cells or neuritin in Foxp3-expressing cells accumulated early plasma cells in germinal centers (GCs) and developed autoantibodies against histones and tissue-specific self-antigens. Upon immunization, these mice also produced increased plasma IgE and IgG1. We show that neuritin is taken up by B cells, causes phosphorylation of numerous proteins, and dampens IgE class switching. Neuritin reduced differentiation of mouse and human GC B cells into plasma cells, downregulated BLIMP-1, and upregulated BCL6. Administration of neuritin to Tfr-deficient mice prevented the accumulation of early plasma cells in GCs. Production of neuritin by Tfr cells emerges as a central mechanism to suppress B cell-driven autoimmunity and IgE-mediated allergies.

Keywords: IgE; autoantibodies; autoimmunity; follicular helper T (Tfh); follicular regulatory T (Tfr); germinal center (GC); neuritin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autoantibodies / immunology
Autoimmunity
B-Lymphocytes / cytology
B-Lymphocytes / immunology*
B-Lymphocytes / metabolism
Cell Differentiation
Forkhead Transcription Factors / genetics
Forkhead Transcription Factors / metabolism
GPI-Linked Proteins / metabolism
Germinal Center / immunology
Germinal Center / metabolism
Histones / immunology
Immunoglobulin Class Switching
Immunoglobulin E / blood
Immunoglobulin E / immunology
Immunoglobulin G / blood
Immunoglobulin G / immunology
Mice
Mice, Inbred C57BL
Mice, Knockout
Nerve Tissue Proteins / metabolism*
Phosphorylation
Plasma Cells / cytology
Plasma Cells / immunology
Plasma Cells / metabolism
Positive Regulatory Domain I-Binding Factor 1 / genetics
Positive Regulatory Domain I-Binding Factor 1 / metabolism
Proto-Oncogene Proteins c-bcl-6 / genetics
Proto-Oncogene Proteins c-bcl-6 / metabolism
T-Lymphocytes, Regulatory / cytology
T-Lymphocytes, Regulatory / immunology*
T-Lymphocytes, Regulatory / metabolism

Substances

Autoantibodies
Bcl6 protein, mouse
Forkhead Transcription Factors
Foxp3 protein, mouse
GPI-Linked Proteins
Histones
Immunoglobulin G
Nerve Tissue Proteins
Nrn1 protein, mouse
Prdm1 protein, mouse
Proto-Oncogene Proteins c-bcl-6
Immunoglobulin E
Positive Regulatory Domain I-Binding Factor 1