IL-21 restricts T follicular regulatory T cell proliferation through Bcl-6 mediated inhibition of responsiveness to IL-2

Christoph Jandl; Sue M Liu; Pablo F Cañete; Joanna Warren; William E Hughes; Alexis Vogelzang; Kylie Webster; Maria E Craig; Gulbu Uzel; Alexander Dent; Polina Stepensky; Bärbel Keller; Klaus Warnatz; Jonathan Sprent; Cecile King

doi:10.1038/ncomms14647

IL-21 restricts T follicular regulatory T cell proliferation through Bcl-6 mediated inhibition of responsiveness to IL-2

Nat Commun. 2017 Mar 17:8:14647. doi: 10.1038/ncomms14647.

Authors

Christoph Jandl^{1

2}, Sue M Liu^{1

2}, Pablo F Cañete³, Joanna Warren¹, William E Hughes¹, Alexis Vogelzang¹, Kylie Webster^{1

2}, Maria E Craig^{4

5}, Gulbu Uzel⁶, Alexander Dent⁷, Polina Stepensky⁸, Bärbel Keller⁹, Klaus Warnatz⁹, Jonathan Sprent^{1

2}, Cecile King^{1

2}

Affiliations

¹ Department of Immunology, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales 2010, Australia.
² Department of Medicine, St Vincent's Clinical School, University of NSW, Sydney, New South Wales 2010, Australia.
³ Division of Immunology and Genetics, John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory 2601, Australia.
⁴ Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, Locked Bag 4001, Westmead, New South Wales 2145, Australia.
⁵ School of Women's and Children's Health, University of New South Wales, High Street, Randwick, Sydney, New South Wales 2031, Australia.
⁶ Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-9806, USA.
⁷ Department of Microbiology and Immunology, Indiana University School of Medicine, 635 Barnhill Drive, MS 420, Indianapolis, Indiana 46202, USA.
⁸ Pediatric Hematology-Oncology and Bone Marrow Transplantation, Hadassah Hebrew University Hospital, Kiryat Hadassah, POB 12000, Jerusalem 91120, Israel.
⁹ Center for Chronic Immunodeficiency (CCI), University Medical Center and University of Freiburg, Breisacher Strasse 117, 79106 Freiburg, Germany.

Abstract

T follicular regulatory (Tfr) cells control the magnitude and specificity of the germinal centre reaction, but how regulation is contained to ensure generation of high-affinity antibody is unknown. Here we show that this balance is maintained by the reciprocal influence of interleukin (IL)-2 and IL-21. The number of IL-2-dependent FoxP3⁺ regulatory T cells is increased in the peripheral blood of human patients with loss-of-function mutations in the IL-21 receptor (IL-21R). In mice, IL-21:IL-21R interactions influence the phenotype of T follicular cells, reducing the expression of CXCR4 and inhibiting the expansion of Tfr cells after T-cell-dependent immunization. The negative effect of IL-21 on Tfr cells in mice is cell intrinsic and associated with decreased expression of the high affinity IL-2 receptor (CD25). Bcl-6, expressed in abundance in Tfr cells, inhibits CD25 expression and IL-21-mediated inhibition of CD25 is Bcl-6 dependent. These findings identify a mechanism by which IL-21 reinforces humoral immunity by restricting Tfr cell proliferation.

Publication types

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

MeSH terms

Adolescent
Animals
Cell Proliferation / genetics*
Child
Female
Humans
Immunity, Humoral / genetics*
Immunity, Humoral / immunology
Immunologic Deficiency Syndromes / genetics
Infant
Interleukin-2 / immunology*
Interleukin-21 Receptor alpha Subunit / genetics*
Interleukin-21 Receptor alpha Subunit / immunology
Interleukins / genetics*
Interleukins / immunology
Male
Mice
Mice, Knockout
Proto-Oncogene Proteins c-bcl-6 / immunology*
Receptors, CXCR4 / immunology
T-Lymphocytes, Regulatory / immunology*

Substances

CXCR4 protein, mouse
IL21R protein, human
Il21r protein, mouse
Interleukin-2
Interleukin-21 Receptor alpha Subunit
Interleukins
Proto-Oncogene Proteins c-bcl-6
Receptors, CXCR4
interleukin-21