LAG-3 Inhibitory Receptor Expression Identifies Immunosuppressive Natural Regulatory Plasma Cells

• Published in: Immunity (Cambridge, Mass.) Vol. 49; no. 1; pp. 120 - 133.e9
• Main Authors: Lino, Andreia C., Dang, Van Duc, Lampropoulou, Vicky, Welle, Anna, Joedicke, Jara, Pohar, Jelka, Simon, Quentin, Thalmensi, Jessie, Baures, Aurelia, Flühler, Vinciane, Sakwa, Imme, Stervbo, Ulrik, Ries, Stefanie, Jouneau, Luc, Boudinot, Pierre, Tsubata, Takeshi, Adachi, Takahiro, Hutloff, Andreas, Dörner, Thomas, Zimber-Strobl, Ursula, de Vos, Alex F., Dahlke, Katja, Loh, Gunnar, Korniotis, Sarantis, Goosmann, Christian, Weill, Jean-Claude, Reynaud, Claude-Agnès, Kaufmann, Stefan H.E., Walter, Jörn, Fillatreau, Simon
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17-07-2018; Elsevier Limited; Elsevier; Cell Press
• Subjects: Animals; Antigens, CD - genetics; Antigens, CD - immunology; B cells; B-cell receptor; B-Lymphocyte Subsets - immunology; BCR; Binding sites; CD200 antigen; CD223 antigen; CD72; checkpoint receptor; Deoxyribonucleic acid; DNA; DNA methylation; Epigenesis, Genetic; Female; Gene Expression; Gene Expression Profiling; Genes; Genomes; immune regulation; Immunity; Immunoglobulins; Immunological memory; Immunosuppression; Immunosuppressive agents; infection; Infections; Interleukin 1; Interleukin 10; Interleukin-10 - biosynthesis; Interleukin-10 - genetics; LAG-3; Life Sciences; Lymphocyte Activation; Lymphocytes; Lymphocytes B; Lymphocytes T; Male; Mice; Microbiota; Morphology; natural regulatory plasma cell; PD-L1 protein; Plasma cells; Plasma Cells - immunology; Plasma Cells - physiology; Receptor mechanisms; Receptors; Receptors, Antigen, B-Cell - metabolism; Regulation; Salmonella; Salmonella Infections, Animal - immunology; Signal Transduction; T-Lymphocytes - immunology; TLR; Toll-like receptors; Toll-Like Receptors - metabolism; Up-Regulation - genetics; Vaccine efficacy; Vaccines - immunology; United States > US; BCR; infection; CD72; LAG-3; natural regulatory plasma cell; B cells; TLR; plasma cells; checkpoint receptor; interleukin-10; immune regulation; generation; il-10; transcription factor; differentiation; autoimmunity; protective immunity i; CD4(+) T-CELLS; b-cells; gene-expression; n-vivo
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2018.06.007

B lymphocytes can suppress immunity through interleukin (IL)-10 production in infectious, autoimmune, and malignant diseases. Here, we have identified a natural plasma cell subset that distinctively expresses the inhibitory receptor LAG-3 and mediates this function in vivo. These plasma cells also express the inhibitory receptors CD200, PD-L1, and PD-L2. They develop from various B cell subsets in a B cell receptor (BCR)-dependent manner independently of microbiota in naive mice. After challenge they upregulate IL-10 expression via a Toll-like receptor-driven mechanism within hours and without proliferating. This function is associated with a unique transcriptome and epigenome, including the lowest amount of DNA methylation at the Il10 locus compared to other B cell subsets. Their augmented accumulation in naive mutant mice with increased BCR signaling correlates with the inhibition of memory T cell formation and vaccine efficacy after challenge. These natural regulatory plasma cells may be of broad relevance for disease intervention.
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•LAG-3 expression identifies natural regulatory plasma cells•LAG-3+CD138hi plasma cells express IL-10 within hours of stimulation•LAG-3+CD138hi plasma cells have a unique epigenome poised to express IL-10•LAG-3+CD138hi plasma cells develop via an antigen-specific mechanism
Plasma cells secrete antibodies and play a key role in host defense against infection. Lino et al. identify a novel subset of natural regulatory plasma cells characterized by the expression of LAG-3 that develops at steady state independently of microbiota, and respond to innate stimulation by producing immunosuppressive IL-10.