Functional STAT3 deficiency compromises the generation of human T follicular helper cells

Author:

Ma Cindy S.12,Avery Danielle T.1,Chan Anna1,Batten Marcel12,Bustamante Jacinta34,Boisson-Dupuis Stephanie35,Arkwright Peter D.6,Kreins Alexandra Y.5,Averbuch Diana7,Engelhard Dan7,Magdorf Klaus8,Kilic Sara S.9,Minegishi Yoshiyuki10,Nonoyama Shigeaki11,French Martyn A.1213,Choo Sharon14,Smart Joanne M.14,Peake Jane15,Wong Melanie16,Gray Paul17,Cook Matthew C.181920,Fulcher David A.21,Casanova Jean-Laurent35,Deenick Elissa K.12,Tangye Stuart G.12

Affiliation:

1. Immunology Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia;

2. St Vincent's Clinical School, University of New South Wales, Sydney, Australia;

3. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Inserm U550, Necker Medical School, Université Paris Descartes, Paris, France;

4. Center for the Study of Primary Immunodeficiencies, Assistance Publique des Hôpitaux de Paris (AP-HP), Necker Hospital, Paris, France;

5. Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY;

6. University of Manchester, Royal Manchester Children's Hospital, Manchester, United Kingdom;

7. Department of Pediatrics and Pediatric Infectious Diseases, Hadassah-Hebrew University Medical Centre, Ein-Kerem, Jerusalem, Israel;

8. Department of Pediatric Pneumology and Immunology, Charité, Humboldt University of Berlin, Berlin, Germany;

9. Department of Pediatrics, Uludag University School of Medicine, Bursa, Turkey;

10. Department of Immune Regulation, Tokyo Medical and Dental University Graduate School, Tokyo, Japan;

11. Department of Pediatrics, National Defense Medical College, Saitama, Japan;

12. Department of Clinical Immunology, Royal Perth Hospital, Perth, Australia;

13. School of Pathology and Laboratory Medicine, University of Western Australia, Perth, Australia;

14. Department of Allergy and Immunology, Royal Children's Hospital, Melbourne, Australia;

15. Department of Paediatrics and Child Health, Royal Children's Hospital Brisbane, Brisbane, Australia;

16. Department of Immunology, Childrens' Hospital at Westmead, Australia;

17. University of New South Wales School of Women's and Children's Health, NSW, Australia;

18. Australian National University Medical School, Australian National University, Canberra, Australia;

19. John Curtin School of Medical Research, Australian National University, Canberra, Australia;

20. Department of Immunology, The Canberra Hospital, Canberra, Australia; and

21. Department of Immunology, Institute of Clinical Pathology and Medical Research, Westmead Hospital, Westmead, Australia

Abstract

Abstract T follicular helper (Tfh) cells are critical for providing the necessary signals to induce differentiation of B cells into memory and Ab-secreting cells. Accordingly, it is important to identify the molecular requirements for Tfh cell development and function. We previously found that IL-12 mediates the differentiation of human CD4+ T cells to the Tfh lineage, because IL-12 induces naive human CD4+ T cells to acquire expression of IL-21, BCL6, ICOS, and CXCR5, which typify Tfh cells. We have now examined CD4+ T cells from patients deficient in IL-12Rβ1, TYK2, STAT1, and STAT3 to further explore the pathways involved in human Tfh cell differentiation. Although STAT1 was dispensable, mutations in IL12RB1, TYK2, or STAT3 compromised IL-12–induced expression of IL-21 by human CD4+ T cells. Defective expression of IL-21 by STAT3-deficient CD4+ T cells resulted in diminished B-cell helper activity in vitro. Importantly, mutations in STAT3, but not IL12RB1 or TYK2, also reduced Tfh cell generation in vivo, evidenced by decreased circulating CD4+CXCR5+ T cells. These results highlight the nonredundant role of STAT3 in human Tfh cell differentiation and suggest that defective Tfh cell development and/or function contributes to the humoral defects observed in STAT3-deficient patients.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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