IL-27 supports germinal center function by enhancing IL-21 production and the function of T follicular helper cells

Marcel Batten; Nandhini Ramamoorthi; Noelyn M Kljavin; Cindy S Ma; Jennifer H Cox; Hart S Dengler; Dimitry M Danilenko; Patrick Caplazi; Melanie Wong; David A Fulcher; Matthew C Cook; Cecile King; Stuart G Tangye; Frederic J de Sauvage; Nico Ghilardi

doi:10.1084/jem.20100064

IL-27 supports germinal center function by enhancing IL-21 production and the function of T follicular helper cells

J Exp Med. 2010 Dec 20;207(13):2895-906. doi: 10.1084/jem.20100064. Epub 2010 Nov 22.

Authors

Marcel Batten¹, Nandhini Ramamoorthi, Noelyn M Kljavin, Cindy S Ma, Jennifer H Cox, Hart S Dengler, Dimitry M Danilenko, Patrick Caplazi, Melanie Wong, David A Fulcher, Matthew C Cook, Cecile King, Stuart G Tangye, Frederic J de Sauvage, Nico Ghilardi

Affiliation

¹ Garvan Institute of Medical Research, Darlinghurst, Sydney NSW 2010, Australia. m.batten@garvan.org.au

Abstract

Maturation and selection of high-affinity B cell clones in the germinal center (GC) relies on support from T follicular helper (T(FH)) cells. T(FH) cells are characterized by their localization to the B cell follicle and their high expression of the costimulatory molecules ICOS and PD1 and the cytokine IL-21, which promotes immunoglobulin (Ig) class switching and production by B cells. We show that the heterodimeric cytokine IL-27 is critical for the function of T(FH) cells and for normal and pathogenic GC responses. IL-27 signaling to T cells results in the production of IL-21, a known autocrine factor for the maintenance of T(FH) cells, in a STAT3-dependent manner. IL-27 also enhances the survival of activated CD4(+) T cells and the expression of T(FH) cell phenotypic markers. In vivo, expression of the IL-27Rα chain is required to support IL-21 production and T(FH) cell survival in a T cell-intrinsic manner. The production of high-affinity antibodies is reduced, and pristane-elicited autoantibodies and glomerulonephritis are significantly diminished, in Il27ra(-/-) mice. Together, our data show a nonredundant role for IL-27 in the development of T cell-dependent antibody responses.

Publication types

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

MeSH terms

Adoptive Transfer
Animals
Bone Marrow / immunology
Bone Marrow / metabolism
Bone Marrow Transplantation
CD4-Positive T-Lymphocytes / immunology
CD4-Positive T-Lymphocytes / metabolism
CD4-Positive T-Lymphocytes / transplantation
Cells, Cultured
Female
Flow Cytometry
Gene Expression / drug effects
Germinal Center / drug effects
Germinal Center / immunology*
Germinal Center / metabolism
Interleukins / genetics
Interleukins / immunology*
Interleukins / metabolism*
Interleukins / pharmacology
Lupus Erythematosus, Systemic / chemically induced
Lupus Erythematosus, Systemic / immunology
Male
Mice
Mice, 129 Strain
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Receptors, Cytokine / deficiency
Receptors, Cytokine / genetics
Receptors, Cytokine / immunology
Receptors, Interleukin
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction / immunology
T-Lymphocytes, Helper-Inducer / drug effects
T-Lymphocytes, Helper-Inducer / immunology*
T-Lymphocytes, Helper-Inducer / metabolism
Terpenes
Transplantation Chimera / immunology

Substances

Il27 protein, mouse
Il27ra protein, mouse
Interleukins
Receptors, Cytokine
Receptors, Interleukin
Terpenes
pristane
interleukin-21