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Plasma cells require autophagy for sustainable immunoglobulin production

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.

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Figure 1: High autophagic activity during PC differentiation and in bone marrow PCs.
Figure 2: Differentiating Atg5f/fCD19-Cre PCs have higher expression of ER-resident proteins and immunoglobulins than do Atg5f/f PCs.
Figure 3: Differentiating Atg5f/fCD19-Cre PCs have a larger ER and an enhanced ER stress response.
Figure 4: Autophagy deficiency increases Blimp-1 expression and immunoglobulin production.
Figure 5: Atg5f/fCD19-Cre ASCs have less ATP and undergo more death.
Figure 6: Defective response to pneumococcal antigens in Atg5f/fCD19-Cre mice.
Figure 7: Autophagy is required in bone marrow PCs.

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Acknowledgements

We thank I. Braakman (University of Utrecht) for anti-PDI antiserum; N. Mizushima (Tokyo University) for GFP-LC3 mice; H.W. Virgin (Washington University) for Atg5f/fCD19-Cre mice; H. Auner, A. Bachi, M. Bertolotti, P. Cascio, P. Dellabona, F. Fontana, J. Garcia, M. Glickman, M. Iannacone, L. Maiuri, A. Manfredi, G. Merlini, A. Mondino, A. Orsi, L. Rampoldi, I. Rowe, S. Tooze, E. Tonti and E. van Anken for discussions and suggestions; T. Pengo, C. Covino and the staff of the Advanced Light and Electron Microscopy Bioimaging Center for support with microscopy; E. Canonico and I. Muradore for cell sorting; L. Spagnuolo for immunohistochemistry; and F. Loro for secretarial assistance. Supported by the Italian Ministry of Health (S. Casola; and Giovani Ricercatori 1143560 to S. Cenci), the Multiple Myeloma Research Foundation (S. Cenci), the Italian Association for Cancer Research (S. Casola; and Special Program Molecular Clinical Oncology 5 per mille 9965 to R.S. and S. Cenci), the Giovanni Armenise-Harvard Foundation Career Development Program (S. Casola) and the Italian Foundation for Cancer Research (S. Casola).

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N.P., S. Casola, R.S. and S. Cenci designed experiments; N.P., M.S., L.O., E. Milan, E.Mariani, F.M., A.R., C.F., A.M., E.P., U.O. and M.P. did the experiments; and N.P., S. Casola and S. Cenci analyzed data and wrote the paper.

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Correspondence to Simone Cenci.

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N.P., M.S. and S.Ce. have filed a patent related to the research presented here.

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Pengo, N., Scolari, M., Oliva, L. et al. Plasma cells require autophagy for sustainable immunoglobulin production. Nat Immunol 14, 298–305 (2013). https://doi.org/10.1038/ni.2524

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