Nonredundant roles for B cell-derived IL-10 in immune counter-regulation.
IL-10 plays a central role in restraining the vigor of inflammatory responses, but the critical cellular sources of this counter-regulatory cytokine remain speculative in many disease models. Using a novel IL-10 transcriptional reporter mouse, we found an unexpected predominance of B cells (including plasma cells) among IL-10-expressing cells in peripheral lymphoid tissues at baseline and during diverse models of in vivo immunological challenge. Use of a novel B cell-specific IL-10 knockout mouse revealed that B cell-derived IL-10 nonredundantly decreases virus-specific CD8(+) T cell responses and plasma cell expansion during murine cytomegalovirus infection and modestly restrains immune activation after challenge with foreign Abs to IgD. In contrast, no role for B cell-derived IL-10 was evident during endotoxemia; however, although B cells dominated lymphoid tissue IL-10 production in this model, myeloid cells were dominant in blood and liver. These data suggest that B cells are an underappreciated source of counter-regulatory IL-10 production in lymphoid tissues, provide a clear rationale for testing the biological role of B cell-derived IL-10 in infectious and inflammatory disease, and underscore the utility of cell type-specific knockouts for mechanistic limning of immune counter-regulation.
Madan
Rajat
R
Division of Molecular Immunology, Cincinnati Children's Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.
Demircik
Filiz
F
Surianarayanan
Sangeetha
S
Allen
Jessica L
JL
Divanovic
Senad
S
Trompette
Aurelien
A
Yogev
Nir
N
Gu
Yuanyuan
Y
Khodoun
Marat
M
Hildeman
David
D
Boespflug
Nicholas
N
Fogolin
Mariela B
MB
Gröbe
Lothar
L
Greweling
Marina
M
Finkelman
Fred D
FD
Cardin
Rhonda
R
Mohrs
Markus
M
Müller
Werner
W
Waisman
Ari
A
Roers
Axel
A
Karp
Christopher L
CL
D000818:Animals; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000821:virology; D004195:Disease Models, Animal; D005260:Female; D006566:Herpesviridae Infections / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000502:physiology; D016753:Interleukin-10 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008221:Lymphoid Tissue / Q000276:immunology / Q000473:pathology / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018146:Muromegalovirus / Q000276:immunology; D041681:NIH 3T3 Cells
D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016753:Interleukin-10