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

Abstract

SummaryB 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.

Cholesterol metabolism drives regulatory B cell function

“…Downstream, PI3K and ERK signals appear to be important for IL-10 expression 14,15 . This is in broad agreement with in vivo data from mouse models suggesting that both TLR and CD40 signals are required for the induction of 50 IL-10 in response to inflammatory stimuli 3,13 . However, precise details of the signaling cascades or cellular profiles underpinning the induction of a regulatory program in B cells are poorly understood.Control of immune cell metabolism is critical in regulating fundamental immunological processes 16,17 .…”

“…Immunosuppressive B cells form a critical component of the immune regulatory compartment 1,2 . It is thought that their suppressive capacity derives mainly from their ability to produce IL-10, and in the absence of any lineage marker, this is considered a hallmark of regulatory B cells [3][4][5][6] . Their functional importance has been well described in murine models of disease, demonstrating a potent regulatory capacity across a number of contexts including infection, cancer, and autoimmune disease 3,[7][8][9][10] .…”

Loss of BAP1 expression is associated with an immunosuppressive microenvironment in uveal melanoma, with implications for immunotherapy development

“…The low expression of ICRs LAG-3 and CTLA-4 among the majority of T-cell clusters suggests that these lymphocytes may not be exhausted but exist in a lower activation state in pUM [80][81][82][83]. Increased transcriptome levels of LAG-3 in the TCGA-UM study could be linked with LAG-3 expression among CD25 + B-cell clusters as evidenced by mass cytometry, suggesting a memory and natural regulatory phenotype for these cells [84,85]. Moreover, higher expression of IDO1 in both pUM and mUM suggests this molecule as an important adjuvant target for immunotherapy using ICIs, since IDO1 blockade has been shown to synergise the therapeutic effector of both CTLA-4 and PD1/PD-L1 inhibitors [61].…”

Plasma cells: You are what you eat

“…Thus, in the context of the findings by Amanna and colleagues, we conclude that the different half-lives of antibody production after vaccination or infection are due to heterogeneity in the lifespan of the plasma cells. 26 These multiple phenotypes should to be considered and integrated with our explanation of plasma cell longevity and heterogeneity. 14,15 Plasma cell lifespan and anatomical location are properties often used to distinguish antibody-secreting cell subsets.…”

“…L AG-3 + plasma cells were found to secrete Interleukin-10 (IL- 10) and exhibit a more natural regulatory phenotype as compared to LAG3-plasma cells. 26 These multiple phenotypes should to be considered and integrated with our explanation of plasma cell longevity and heterogeneity.…”