Plasma cells require autophagy for sustainable immunoglobulin production.
The role of autophagy in plasma cells is unknown. Here we found notable autophagic activity in both differentiating and long-lived plasma cells and investigated its function through the use of mice with conditional deficiency in the essential autophagic molecule Atg5 in B cells. Atg5(-/-) differentiating plasma cells had a larger endoplasmic reticulum (ER) and more ER stress signaling than did their wild-type counterparts, which led to higher expression of the transcriptional repressor Blimp-1 and immunoglobulins and more antibody secretion. The enhanced immunoglobulin synthesis was associated with less intracellular ATP and more death of mutant plasma cells, which identified an unsuspected autophagy-dependent cytoprotective trade-off between immunoglobulin synthesis and viability. In vivo, mice with conditional deficiency in Atg5 in B cells had defective antibody responses, complete selection in the bone marrow for plasma cells that escaped Atg5 deletion and fewer antigen-specific long-lived bone marrow plasma cells than did wild-type mice, despite having normal germinal center responses. Thus, autophagy is specifically required for plasma cell homeostasis and long-lived humoral immunity.
Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy.
Niccolò
N
Pengo
Maria
M
Scolari
Laura
L
Oliva
Enrico
E
Milan
Federica
F
Mainoldi
Andrea
A
Raimondi
Claudio
C
Fagioli
Arianna
A
Merlini
Elisabetta
E
Mariani
Elena
E
Pasqualetto
Ugo
U
Orfanelli
Maurilio
M
Ponzoni
Roberto
R
Sitia
Stefano
S
Casola
Simone
S
Cenci
D000255:Adenosine Triphosphate; D000818:Animals; D000917:Antibody Formation; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000276:immunology; D002454:Cell Differentiation; D004721:Endoplasmic Reticulum / Q000235:genetics; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D018858:Germinal Center / Q000276:immunology; D006706:Homeostasis; D007136:Immunoglobulins / Q000096:biosynthesis*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics*; D010950:Plasma Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D000074462:Positive Regulatory Domain I-Binding Factor 1; D014157:Transcription Factors / Q000096:biosynthesis
C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D007136:Immunoglobulins; D008869:Microtubule-Associated Proteins; C513258:Prdm1 protein, mouse; D014157:Transcription Factors; D000255:Adenosine Triphosphate; D000074462:Positive Regulatory Domain I-Binding Factor 1