IL-12p35 induces expansion of IL-10 and IL-35-expressing regulatory B cells and ameliorates autoimmune disease

Ivy M. Dambuza, Chang He, Jin Kyeong Choi, Cheng-Rong Yu, Renxi Wang, Mary J. Mattapallil, Paul T. Wingfield, Rachel R. Caspi and Charles E. Egwuagu ()
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Ivy M. Dambuza: Molecular Immunology Section, Laboratory of Immunology, National Eye Institute (NEI), National Institutes of Health (NIH)
Chang He: Molecular Immunology Section, Laboratory of Immunology, National Eye Institute (NEI), National Institutes of Health (NIH)
Jin Kyeong Choi: Molecular Immunology Section, Laboratory of Immunology, National Eye Institute (NEI), National Institutes of Health (NIH)
Cheng-Rong Yu: Molecular Immunology Section, Laboratory of Immunology, National Eye Institute (NEI), National Institutes of Health (NIH)
Renxi Wang: Molecular Immunology Section, Laboratory of Immunology, National Eye Institute (NEI), National Institutes of Health (NIH)
Mary J. Mattapallil: Immunoregulation Section, Laboratory of Immunology, NEI, NIH
Paul T. Wingfield: Protein Expression Laboratory, National Institute Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health
Rachel R. Caspi: Immunoregulation Section, Laboratory of Immunology, NEI, NIH
Charles E. Egwuagu: Molecular Immunology Section, Laboratory of Immunology, National Eye Institute (NEI), National Institutes of Health (NIH)

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract Interleukin 35 (IL-35) is a heterodimeric cytokine composed of IL-12p35 and Ebi3 subunits. IL-35 suppresses autoimmune diseases while preventing host defense to infection and promoting tumor growth and metastasis by converting resting B and T cells into IL-10-producing and IL-35-producing regulatory B (Breg) and T (Treg) cells. Despite sharing the IL-12p35 subunit, IL-12 (IL-12p35/IL-12p40) promotes inflammatory responses whereas IL-35 (IL-12p35/Ebi3) induces regulatory responses, suggesting that IL-12p35 may have unknown intrinsic immune-regulatory functions regulated by its heterodimeric partner. Here we show that the IL-12p35 subunit has immunoregulatory functions hitherto attributed to IL-35. IL-12p35 suppresses lymphocyte proliferation, induces expansion of IL-10-expressing and IL-35-expressing B cells and ameliorates autoimmune uveitis in mice by antagonizing pathogenic Th17 responses. Recapitulation of essential immunosuppressive activities of IL-35 indicates that IL-12p35 may be utilized for in vivo expansion of Breg cells and autologous Breg cell immunotherapy. Furthermore, our uveitis data suggest that intrinsic immunoregulatory activities of other single chain IL-12 subunits might be exploited to treat other autoimmune diseases.

Date: 2017
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DOI: 10.1038/s41467-017-00838-4

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