IL-27 Directly Enhances Germinal Center B Cell Activity and Potentiates Lupus in Sanroque Mice.
Germinal centers (GC) give rise to high-affinity and long-lived Abs and are critical in immunity and autoimmunity. IL-27 supports GCs by promoting survival and function of T follicular helper cells. We demonstrate that IL-27 also directly enhances GC B cell function. Exposure of naive human B cells to rIL-27 during in vitro activation enhanced their differentiation into CD20+CD38+CD27lowCD95+CD10+cells, consistent with the surface marker phenotype of GC B cells. This effect was inhibited by loss-of-function mutations in STAT1 but not STAT3 To extend these findings, we studied the in vivo effects of IL-27 signals to B cells in the GC-driven Roquinsan/sanlupus mouse model. Il27ra-/-Roquinsan/sanmice exhibited significantly reduced GCs, IgG2a(c)+autoantibodies, and nephritis. Mixed bone marrow chimeras confirmed that IL-27 acts through B cell- and CD4+T cell-intrinsic mechanisms to support GCs and alter the production of pathogenic Ig isotypes. To our knowledge, our data provide the first evidence that IL-27 signals directly to B cells promote GCs and support the role of IL-27 in lupus.
Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia.|St. Vincent's Clinical School, University of New South Wales, Sydney, New South Wales 2052, Australia.
Dipti
D
Vijayan
Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia.
Norhanani
0000-0002-5710-4009
N
Mohd Redzwan
Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia.
Danielle T
DT
Avery
Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia.
Rushika C
RC
Wirasinha
Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia.|St. Vincent's Clinical School, University of New South Wales, Sydney, New South Wales 2052, Australia.
Robert
R
Brink
Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory 2601, Australia.|Department of Renal Medicine, Canberra Hospital, Canberra, Australian Capital Territory 2605, Australia.|Australian National University Medical School, Canberra, Australian Capital Territory 2601, Australia.
Giles
0000-0003-4854-9353
G
Walters
Clinical Immunology, Royal Prince Alfred Hospital, Sydney, New South Wales 2050, Australia.
Stephen
0000-0001-7221-6298
S
Adelstein
Department of Pediatrics, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima 734-8553, Japan.
Masao
0000-0002-2001-822X
M
Kobayashi
University of New South Wales School of Women's and Children's Health, Sydney, New South Wales 2031, Australia.
Paul
P
Gray
Sydney Medical School, University of Sydney, Sydney, New South Wales 2006, Australia.|Chris O'Brien Lifehouse Cancer Centre, Royal Prince Alfred Hospital, Sydney, New South Wales 2050, Australia.
Michael
M
Elliott
Children's Hospital at Westmead, Westmead, New South Wales 2145, Australia; and.
Melanie
M
Wong
Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia.|St. Vincent's Clinical School, University of New South Wales, Sydney, New South Wales 2052, Australia.
Cecile
C
King
Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory 2601, Australia.
Carola G
0000-0001-9799-0298
CG
Vinuesa
Department of Immunology, Genentech Inc., South San Francisco, CA 94080.
Nico
0000-0003-4945-3097
N
Ghilardi
Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia.|St. Vincent's Clinical School, University of New South Wales, Sydney, New South Wales 2052, Australia.
Cindy S
CS
Ma
Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia.|St. Vincent's Clinical School, University of New South Wales, Sydney, New South Wales 2052, Australia.
Stuart G
0000-0002-5360-5180
SG
Tangye
Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia; m.batten@garvan.org.au.|St. Vincent's Clinical School, University of New South Wales, Sydney, New South Wales 2052, Australia.
Marcel
M
Batten
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018858:Germinal Center / Q000276:immunology*; D006801:Humans; D064094:Interleukin-27 / Q000276:immunology / Q000378:metabolism*; D008181:Lupus Nephritis / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018121:Receptors, Cytokine / Q000235:genetics; D018123:Receptors, Interleukin; D050794:STAT1 Transcription Factor / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
C484747:Il27ra protein, mouse; D064094:Interleukin-27; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C501406:Rc3h1 protein, mouse; D044767:Ubiquitin-Protein Ligases