Inducible IL-12-producing B cells regulate Th2-mediated intestinal inflammation.
OBJECTIVE
Our previous studies have identified a B-cell subset that is induced under inflammatory conditions in T-cell receptor alpha knockout (TCRalphaKO) mice and contributes to the attenuation of colitis by producing interleukin (IL)-10. However, it is unclear whether IL-10-producing B cells directly or indirectly regulate inflammation.


METHODS
Cytokine production of purified mesenteric lymph node (MLN) B cells was examined by flow cytometric analysis, enzyme-linked immunosorbent assay, quantitative polymerase chain reaction, and RNase protection assay. To investigate the functional role of IL-12p70 in the pathogenesis of colitis in TCRalphaKO mice, IL-12p35-deficient TCRalpha double knockout mice were generated.


RESULTS
In the absence of B cells or IL-10, IL-12p35 expression was significantly down-regulated in the MLN of TCRalphaKO mice. The expression of IL-12p35 was restored in the recipient B-cell-deficient TCRalpha double knockout (alphamicroDKO) mice by the transfer of B cells capable of producing IL-10. Notably, B cells predominantly produced IL-12p35 in the MLN through the help of IL-10-producing B cells. Functionally, IL-12 is involved in the regulation of the T-helper (Th) 2-mediated inflammation as indicated by the development of much more severe colitis in IL-12p35-deficient TCRalpha double knockout (alphap35DKO) mice compared with TCRalphaKO mice. In addition, transfer of MLN B cells from TCRalphaKO mice but not from alphap35DKO mice suppressed colitis in recipient alphamicroDKO mice.


CONCLUSIONS
These studies have identified a novel IL-12-producing regulatory B-cell subset that develops under Th2-mediated intestinal inflammatory conditions and in the presence of IL-10 and is involved in the regulation of intestinal inflammation.
Sugimoto
Ken
K
Department of Pathology, Immunopathology Unit, Massachusetts General Hospital, Boston 02114, USA.
Ogawa
Atsuhiro
A
Shimomura
Yasuyo
Y
Nagahama
Kiyotaka
K
Mizoguchi
Atsushi
A
Bhan
Atul K
AK
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002908:Chronic Disease; D003092:Colitis / Q000276:immunology* / Q000473:pathology; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D053765:Interleukin-12 Subunit p35 / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism
C408982:CPG-oligonucleotide; D053765:Interleukin-12 Subunit p35; D020381:Interleukin-17; D009838:Oligodeoxyribonucleotides; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma