IL-12 drives the differentiation of human T follicular regulatory cells

Author:

Castaño Diana123ORCID,Wang Sidney12ORCID,Atencio-Garcia Segovia45ORCID,Shields Emily J.45ORCID,Rico Maria C.123ORCID,Sharpe Hannah12ORCID,Bustamante Jacinta6789ORCID,Feng Allan1011ORCID,Le Coz Carole1213ORCID,Romberg Neil212ORCID,Tobias John W.14ORCID,Utz Paul J.1011ORCID,Henrickson Sarah E.1212ORCID,Casanova Jean-Laurent6781516ORCID,Bonasio Roberto45ORCID,Locci Michela12ORCID

Affiliation:

1. Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

2. Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

3. Grupo de Inmunología Celular e Inmunogenética, Instituto de Investigaciones Médicas, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia.

4. Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

5. Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

6. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.

7. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA.

8. Paris Cité University, Imagine Institute, Paris, France.

9. Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children, AP-HP, Paris, France.

10. Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA.

11. Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA, USA.

12. Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

13. Infinity, Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, CNRS, Inserm, Toulouse, France.

14. Penn Genomics and Sequencing Core, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

15. Department of Pediatrics, Necker Hospital for Sick Children, AP-HP, Paris, France.

16. Howard Hughes Medical Institute, New York, NY, USA.

Abstract

T follicular regulatory (T fr ) cells can counteract the B cell helper activity of T follicular helper (T fh ) cells and hinder the production of antibodies against self-antigens or allergens. A mechanistic understanding of the cytokines initiating the differentiation of human regulatory T (T reg ) cells into T fr cells is still missing. Herein, we report that low doses of the pro-T fh cytokine interleukin-12 (IL-12) drive the induction of a T fr cell program on activated human T reg cells while also preserving their regulatory function. Mechanistically, we found that IL-12 led to STAT4 (signal transducer and activator of transcription 4) phosphorylation and binding to IL-12–driven follicular signature genes. Patients with inborn errors of immunity in the IL12RB1 gene presented with a strong decrease in circulating T fr cells and produced higher levels of anti-actin autoantibodies in vivo. Overall, this study unveils IL-12 as an inducer of T fr cell differentiation in vivo and provides an approach for the in vitro generation of human T fr -like cells.

Publisher

American Association for the Advancement of Science (AAAS)

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