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The expanding functional diversity of plasma cells in immunity and inflammation

Cellular & Molecular Immunology volume 17, pages 421–422 (2020)Cite this article

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The generation and function of plasma cells have been well recognized as the central events in humoral immunity. In particular, long-lived plasma cells, characterized by a long lifespan and the lack of cell division, persistently secrete high-affinity antibodies to maintain serum antibody titers in the immune response and autoimmune inflammation. Although the significant expansion of plasma cells is observed during the aging process, autoimmune diseases and chronic infections, the expanding functional diversity and underlying mechanisms of plasma cells remain incompletely understood. Here, we describe recent advances in revealing new functional subsets and phenotypic features of plasma cells in aging and autoimmunity.

Hematopoietic stem cells (HSCs) include lymphoid-biased HSCs (Ly-HSCs) for lymphopoiesis and myeloid-biased counterparts (My-HSCs) for myelopoiesis. Aging results in decreased lymphopoiesis and increased myelopoiesis in the bone marrow with a prominent expansion of My-HSCs, common myeloid progenitors (CMPs), granulocyte-macrophage progenitors (GMPs) and mature myeloid cell subsets.1 Recently, Pioli et al. described a novel function of plasma cells in the age-related increase in myelopoiesis in the bone marrow.2 Significant accumulation of surface IgM+IgA−, IgM−IgA+, and IgM+IgA+ plasma cells was observed in the bone marrow of middle-aged and old mice. The depletion of plasma cells from old mice with anti-mouse CD138 antibodies reduced myelopoiesis to its levels observed in young animals. Anti-mouse CD138 antibody treatment effectively removed B220−CD138+ plasma cells without affecting B220+CD138int IgD− plasmablast counterparts, unlike the effects of isotype-matched antibody-treated old mice. Old mice subjected to plasma cell depletion exhibited dramatically decreased numbers of My-HSCs, CMPs, monocytes, and granulocytes, while no significant change in the numbers of Ly-HSCs was observed. Importantly, the depletion of plasma cells did not alter either lymphopoiesis or myelopoiesis in young bone marrow, indicating the key effects of plasma cell accumulation in age-related myeloid skewing in the bone marrow. Consistently, in vitro experiments confirmed the reduced proportions of CD19+ B lymphocytes but increased CD11b+ myeloid lineage output from Ly-HSCs cocultured with old plasma cells. Furthermore, the addition of old plasma cells significantly enhanced CD11b+ cell production from My-HSCs and suppressed CD19+ B cell generation in common lymphoid progenitor (CLP) cultures. However, supplementation with young plasma cells had no effects on the differentiation of Ly-HSCs and My-HSCs in vitro. Further elucidation of the transcriptional signatures of plasma cells isolated from young and old mice indicated age-associated transcriptional profiles in plasma cells. Notably, increased levels of the pathogen sensors Tlr4, Naip2, and Nod2 and the effector molecules Erk1, Elk1, and Tbk1 were detected in old plasma cells. Accordingly, old plasma cells expressed persistently higher levels of TLR4 than young plasma cells with or without LPS stimulation. In addition, the natural TLR4 ligand LPS has been shown to induce expression of the proinflammatory cytokines Il1b, Il6, Tnf and the chemokines Ccl3 and Cxcl10 in old plasma cells. Interestingly, the depletion of plasma cells with anti-CD138 antibody also triggered alterations in the bone marrow stromal microenvironment. After plasma cell depletion, decreased levels of the inflammatory molecules Il23, Tnfsf14, Tirap, Ly96, Tlr4, Tlr5, Itgb2, and Fos were observed in stromal cells from the bone marrow of old mice. Moreover, blockade of IL-1β and TNF-α markedly decreased myelopoiesis in the bone marrow of old mice, indicating that the proinflammatory cytokines IL-1β and TNF-α contribute significantly to the aging-related inflammatory milieu and myelopoiesis in mouse bone marrow. Together, these seminal findings have identified the novel function of aging-associated plasma cells in modulating both the hematopoietic microenvironment and HSC fate decisions.

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Acknowledgements

This study was supported by grants from the National Natural Science Foundation of China (No. 91842304, 81771761, and 81901635), the Hong Kong SAR Government (No. 17114515), HKU Seed Funding for Strategic Interdisciplinary Research Scheme and the Hong Kong Croucher Foundation (260960116).

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  1. Department of Rheumatology and Immunology, Second Clinical Medical College of Jinan University, Shenzhen People’s Hospital, Shenzhen, China

    Kongyang Ma & Dongzhou Liu

  2. Department of Pathology and Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China

    Kongyang Ma, Xiaohui Wang, Xiang Lin, Fan Xiao & Liwei Lu

  3. Department of Rheumatology, The First Affiliated Hospital and College of Clinical Medicine, Henan University of Science and Technology, Luoyang, China

    Xiaofei Shi & Xin Ma

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  1. Kongyang Ma
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Correspondence to Liwei Lu.

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Ma, K., Wang, X., Shi, X. et al. The expanding functional diversity of plasma cells in immunity and inflammation. Cell Mol Immunol 17, 421–422 (2020). https://doi.org/10.1038/s41423-019-0308-z

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