Plasma Cells Require Autophagy for Sustainable Immunoglobulin Production

Nat Immunol. 2013 Mar;14(3):298-305. doi: 10.1038/ni.2524. Epub 2013 Jan 27.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate
  • Animals
  • Antibody Formation
  • Autophagy*
  • Autophagy-Related Protein 5
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism*
  • Bone Marrow Cells / immunology
  • Cell Differentiation
  • Endoplasmic Reticulum / genetics
  • Endoplasmic Reticulum Stress / genetics
  • Germinal Center / immunology
  • Homeostasis
  • Immunoglobulins / biosynthesis*
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microtubule-Associated Proteins / deficiency
  • Microtubule-Associated Proteins / genetics*
  • Plasma Cells / cytology
  • Plasma Cells / immunology*
  • Plasma Cells / metabolism
  • Positive Regulatory Domain I-Binding Factor 1
  • Transcription Factors / biosynthesis

Substances

  • Atg5 protein, mouse
  • Autophagy-Related Protein 5
  • Immunoglobulins
  • Microtubule-Associated Proteins
  • Prdm1 protein, mouse
  • Transcription Factors
  • Adenosine Triphosphate
  • Positive Regulatory Domain I-Binding Factor 1