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CORRESPONDENCE The expanding functional diversity of plasma cells in and inflammation

Kongyang Ma1,2, Xiaohui Wang2, Xiaofei Shi3, Xiang Lin 2, Fan Xiao2, Xin Ma3, Dongzhou Liu1 and Liwei Lu2 Cellular & Molecular Immunology (2020) 17:421–422; https://doi.org/10.1038/s41423-019-0308-z

The generation and function of plasma cells have been well isolated from young and old mice indicated age-associated recognized as the central events in . In transcriptional profiles in plasma cells. Notably, increased levels particular, long-lived plasma cells, characterized by a long lifespan of the pathogen sensors Tlr4, Naip2, and Nod2 and the effector and the lack of cell division, persistently secrete high-affinity molecules Erk1, Elk1, and Tbk1 were detected in old plasma cells. to maintain serum titers in the immune Accordingly, old plasma cells expressed persistently higher levels response and autoimmune inflammation. Although the significant of TLR4 than young plasma cells with or without LPS stimulation. expansion of plasma cells is observed during the aging process, In addition, the natural TLR4 ligand LPS has been shown to induce autoimmune diseases and chronic infections, the expanding expression of the proinflammatory Il1b, Il6, Tnf and the functional diversity and underlying mechanisms of plasma cells chemokines Ccl3 and Cxcl10 in old plasma cells. Interestingly, the remain incompletely understood. Here, we describe recent depletion of plasma cells with anti-CD138 antibody also triggered advances in revealing new functional subsets and phenotypic alterations in the stromal microenvironment. After

1234567890();,: features of plasma cells in aging and . depletion, decreased levels of the inflammatory Hematopoietic stem cells (HSCs) include lymphoid-biased HSCs molecules Il23, Tnfsf14, Tirap, Ly96, Tlr4, Tlr5, Itgb2, and Fos were (Ly-HSCs) for and myeloid-biased counterparts (My- observed in stromal cells from the bone marrow of old mice. HSCs) for myelopoiesis. Aging results in decreased lymphopoiesis Moreover, blockade of IL-1β and TNF-α markedly decreased and increased myelopoiesis in the bone marrow with a prominent myelopoiesis in the bone marrow of old mice, indicating that the expansion of My-HSCs, common myeloid progenitors (CMPs), proinflammatory cytokines IL-1β and TNF-α contribute signifi- - progenitors (GMPs) and mature myeloid cantly to the aging-related inflammatory milieu and myelopoiesis cell subsets.1 Recently, Pioli et al. described a novel function of in mouse bone marrow. Together, these seminal findings have plasma cells in the age-related increase in myelopoiesis in the identified the novel function of aging-associated plasma cells in bone marrow.2 Significant accumulation of surface IgM+IgA−, modulating both the hematopoietic microenvironment and HSC IgM−IgA+, and IgM+IgA+ plasma cells was observed in the bone fate decisions. marrow of middle-aged and old mice. The depletion of plasma Although the pathogenic role of plasma cells in autoimmune cells from old mice with anti-mouse CD138 antibodies reduced development has been extensively studied, functional subsets of myelopoiesis to its levels observed in young animals. Anti-mouse plasma cells remain partially characterized. Recently, we CD138 antibody treatment effectively removed B220−CD138+ revealed the pathogenic role of the long-lived TLR4+CXCR4+ plasma cells without affecting B220+CD138int IgD− plasmablast plasma cell subset in both patients with systemic counterparts, unlike the effects of -matched antibody- erythematosus (SLE) and mice with experimental lupus.3 treated old mice. Old mice subjected to plasma cell depletion TLR4+CXCR4+ plasma cells, which predominantly secreted exhibited dramatically decreased numbers of My-HSCs, CMPs, anti-dsDNA IgG and triggered nephritis devel- monocytes, and , while no significant change in the opment in immunodeficient RAG-2 mice after their adoptive numbers of Ly-HSCs was observed. Importantly, the depletion of transfer, were significantly expanded in the peripheral plasma cells did not alter either lymphopoiesis or myelopoiesis in and renal tissues of active SLE patients and lupus mice. In young bone marrow, indicating the key effects of plasma cell addition, a long-term BrdU incorporation assay identified accumulation in age-related myeloid skewing in the bone marrow. TLR4+CXCR4+ plasma cells as long-lived plasma cells in lupus Consistently, in vitro experiments confirmed the reduced propor- mice. Remarkably, the blockade of TLR4 with CLI-095 abrogated tions of CD19+ B but increased CD11b+ myeloid secretion in TLR4+CXCR4+ plasma cells and lineage output from Ly-HSCs cocultured with old plasma cells. ameliorated renal damage in lupus mice, indicating the critical Furthermore, the addition of old plasma cells significantly role of TLR4 signaling in modulating autoantibody secretion in enhanced CD11b+ cell production from My-HSCs and suppressed long-lived plasma cells. Moreover, CXCR4 expression may CD19+ generation in common lymphoid progenitor (CLP) contribute to the recruitment of long-lived plasma cells towards cultures. However, supplementation with young plasma cells had inflamed kidneys during lupus pathogenesis. Thus, these no effects on the differentiation of Ly-HSCs and My-HSCs in vitro. findings highlight the pathogenic role of long-lived autoreactive Further elucidation of the transcriptional signatures of plasma cells plasma cells in autoimmune development.

1Department of Rheumatology and Immunology, Second Clinical Medical College of Jinan University, Shenzhen People’s Hospital, Shenzhen, China; 2Department of Pathology and Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China and 3Department of Rheumatology, The First Affiliated Hospital and College of Clinical Medicine, Henan University of Science and Technology, Luoyang, China Correspondence: Liwei Lu ([email protected]) Received: 17 September 2019 Accepted: 22 September 2019 Published online: 24 October 2019

© CSI and USTC 2019 The expanding functional diversity of plasma cells in immunity and. . . K Ma et al. 422 Novel subsets of plasma cells with regulatory functions in infections and autoimmune diseases via the secretion of inhibitory cytokines, including IL-10 and IL-35, were recently characterized.4–6 Notably, hypoxia-inducible factor-1α (HIF-1α) has been identified as a critical transcription factor in IL-10-producing B cells in auto- immune disease.7 Mice with impaired plasma cell differentiation (Prdm1f/fMb1Cre/+ ) showed exacerbated experimental autoimmune encephalomyelitis (EAE) development.4 Previous studies revealed that CD138hi plasmablasts in the draining lymph nodes, but not those in the , were the dominant IL-10-producing B cell subset and negatively regulated autoimmune inflammation in EAE.4 However, splenic CD138hi plasma cells with increased secretion of IL- 35 were shown to possess a regulatory function during EAE development and Salmonella infection.5 Recently, Lino et al. defined a natural regulatory plasma cell subset characterized by expression of the inhibitory receptor -activation gene 3 (LAG-3) that developed at steady state and quickly responded to Salmonella infection by producing IL-10.8 These LAG-3+ B cell counterparts exhibited key attributes of plasma cells with a phenotype of B220−CD138hiBlimp-1hiKi-67− and were the major IL-10-producing B cell subset in the spleen and bone marrow. Further transcriptome + hi Fig. 1 The diverse functions of plasma cells in immunity and analysis revealed the functional features of LAG-3 CD138 plasma inflammation. cells with enriched gene expression of Il10, Lag3, Cd200, Cd273, Klf4, and Bhlhe40 compared with that of LAG-3− plasma cell counterparts. Although LAG-3+CD138hi plasma cells showed the increased regulatory plasma cells produce IL-10 and suppress autoimmune transcription of Klf4, which is expressed in long-lived plasma cells inflammation (Fig. 1). Thus, further characterization of plasma cell in the bone marrow, it is currently unclear whether these subsets is needed to address the key metabolic, transcriptomic nondividing LAG-3+CD138hi plasma cells represent a subset of and epigenetic events that modulate their differentiation and long-lived plasma cell compartments in vivo. Interestingly, single-cell functional diversity in immune homeostasis and disease.12 BCR sequencing revealed a distinct BCR repertoire with increased VH7, VH10, and VH11 segments in LAG-3+CD138hi plasma cells that corresponded to the typical BCR features in B-1a cells.9,10 The ACKNOWLEDGEMENTS + + enrichment of VH11 Vk14 BCRs, which were otherwise expressed This study was supported by grants from the National Natural Science Foundation of by B-1a cells to recognize phosphatidylcholine (PtC), was confirmed China (No. 91842304, 81771761, and 81901635), the Hong Kong SAR Government by flow cytometric analysis of IL-10-producing LAG-3+CD138hi (No. 17114515), HKU Seed Funding for Strategic Interdisciplinary Research Scheme plasma cells. Mechanistically, deficiency of Cd19 and Btk significantly and the Hong Kong Croucher Foundation (260960116). reduced the frequency and number of LAG-3+CD138hi plasma cells αβ fi in vivo. In contrast, Il10, TCR or Cd72 de ciency markedly ADDITIONAL INFORMATION expanded LAG-3+CD138hi plasma cells. This elegant study has demonstrated the regulatory role of LAG-3+CD138hi plasma cells in Competing interests: The authors declare no competing interests. preventing excessive immunopathology. A recent study by Lam et al. reported that the survival of long- REFERENCES lived plasma cells was modulated by pyruvate generation.11 Long- 1. Morrison, S. J. et al. The aging of hematopoietic stem cells. Nat. Med. 2, lived plasma cells were found to harbor a potent mitochondrial 1011–1016 (1996). respiratory capacity when compared with short-lived plasma cells. 2. Pioli, P. D. et al. Plasma cells are obligate effectors of enhanced myelopoiesis in The blockade of pyruvate import with UK5099 skewed the aging bone marrow. Immunity 51, 351–366.e6 (2019). metabolic profiles of long-lived plasma cells, which adopted the 3. Ma, K. et al. 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Immunol. https://doi.org/ metabolic fates with C glucose showed substantial C enrich- 10.1038/s41423-019-0227-z. (2019). ment in mannose for antibody glycosylation in long-lived plasma 7. Meng, X. et al. Hypoxia-inducible factor-1α is a critical transcription factor for IL- cells. These findings reveal the unique metabolic pathways in 10-producing B cells in autoimmune disease. Nat. Commun. 9, 251 (2018). long-lived plasma cells. However, the distinct metabolic features 8. Lino, A. C. et al. LAG-3 inhibitory receptor expression identifies immunosup- of age-associated plasma cells, long-lived autoreactive plasma pressive natural regulatory plasma cells. Immunity 49, 120–133.e9 (2018). cells and regulatory plasma cells remain to be investigated. 9. Graf, R. et al. BCR-dependent lineage plasticity in mature B cells. Science 363, – In summary, the expanding pool of plasma cell subsets may 748 753 (2019). 10. Wang, X. et al. New insights into the significance of the BCR repertoire in B-1 cell harbor phenotypic, metabolic and transcriptional diversity related – fl development and function. Cell Mol. Immunol. 16, 772 773 (2019). to their anti- or proin ammatory functions in aging and 11. Lam, W. Y. et al. Mitochondrial pyruvate import promotes long-term survival of autoimmunity, as revealed by recent findings that TLR-4- antibody-secreting plasma cells. Immunity 45,60–73 (2016). expressing long-lived plasma cells persistently secrete autoanti- 12. Wu, H. et al. Epigenetic regulation in B-cell maturation and its dysregulation in bodies and proinflammatory cytokines, while LAG-3-expressing autoimmunity. Cell Mol. Immunol. 15, 676–684 (2018).

Cellular & Molecular Immunology (2020) 17:421 – 422