APRIL secreted by neutrophils binds to heparan sulfate proteoglycans to create plasma cell niches in human mucosa.
The bone marrow constitutes a favorable environment for long-lived antibody-secreting plasma cells, providing blood-circulating antibody. Plasma cells are also present in mucosa-associated lymphoid tissue (MALT) to mediate local frontline immunity, but how plasma cell survival there is regulated is not known. Here we report that a proliferation-inducing ligand (APRIL) promoted survival of human upper and lower MALT plasma cells by upregulating expression of the antiapoptotic proteins bcl-2, bcl-xL, and mcl-1. The in situ localization of APRIL was consistent with such a prosurvival role in MALT. In upper MALT, tonsillar epithelium produced APRIL. Upon infection, APRIL production increased considerably when APRIL-secreting neutrophils recruited from the blood infiltrated the crypt epithelium. Heparan sulfate proteoglycans (HSPGs) retained secreted APRIL in the subepithelium of the infected zone to create APRIL-rich niches, wherein IgG-producing plasma cells accumulated. In lower MALT, neutrophils were the unique source of APRIL, giving rise to similar niches for IgA-producing plasmocytes in villi of lamina propria. Furthermore, we found that mucosal humoral immunity in APRIL-deficient mice is less persistent than in WT mice. Hence, production of APRIL by inflammation-recruited neutrophils may create plasma cell niches in MALT to sustain a local antibody production.
Huard
Bertrand
B
Division of Hematology, Geneva University Hospital, Department of Patho-Immunology, Geneva University Medical Center, Geneva, Switzerland. bertrand.huard@medecine.unige.ch
McKee
Thomas
T
Bosshard
Carine
C
Durual
Stéphane
S
Matthes
Thomas
T
Myit
Samir
S
Donze
Olivier
O
Frossard
Christophe
C
Chizzolini
Carlo
C
Favre
Christiane
C
Zubler
Rudolf
R
Guyot
Jean Philippe
JP
Schneider
Pascal
P
Roosnek
Eddy
E
D002460:Cell Line; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000166:cytology; D009092:Mucous Membrane / Q000276:immunology*; D009504:Neutrophils / Q000378:metabolism*; D010950:Plasma Cells / Q000276:immunology*; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000235:genetics / Q000378:metabolism*
D019812:Heparan Sulfate Proteoglycans; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13