Biology subjects

Tsuji, N. M.

Publications and source records attributed to Tsuji, N. M..

2 recordsLinked to original sources

bioRxiv2024

Lactococcus lactis subsp. cremoris C60 creates a type I regulatory T cell-dominant anti-inflammatory intestinal environment through functional modification of dendritic cells

Lactic acid bacteria (LAB)-mediated probiotics have the capability to modulate intestinal immunity, creating an anti-inflammatory environment. Among the immune-modulatory effects, interleukin (IL)-10-producing CD4+ T cells are often discussed for their anti-inflammatory roles. While regulatory T cells (Tregs) are a well-known subset, type I regulatory T (Tr1) cells, which also produce abundant IL-10, receive less attention in LAB-induced anti-inflammatory effects. Here, we report that Lactococcus lactis subsp. cremoris C60, a probiotic LAB strain, increases IL-10-producing Tr1 cells in the intestinal environment, contributing to resistance against inflammatory conditions such as dextran sodium sulfate (DSS)-induced colitis. Intragastric administration of heat-killed (HK)-C60 significantly increased IL-10+CD4+ T cells in intestinal tissues compared to control treatment. These populations predominantly consisted of Forkhead box protein P3 (Foxp3)-negative cells, indicating that Tr1 cells were primarily expanded by HK-C60 stimulation. Further analysis revealed that IL-10+ Tr1 cells could be classified into two major subpopulations: IL-10 single-positive (SP) and IFN-{gamma}/IL-10 double-positive (DP) cells. An in vitro co-culture system using CD4+ T cells and bone marrow-derived dendritic cells (BMDCs) demonstrated that HK-C60 stimulation modified dendritic cell function, promoting Tr1 cell differentiation. Moreover, pro-inflammatory IFN-{gamma}+CD4+ T (Th1) cells differentiated into IL-10+ Tr1 cells in the presence of HK-C60-stimulated BMDCs, with the effect being particularly pronounced in DP Tr1 cells. HK-C60-administration attenuated inflammation and reduced pro-inflammatory leukocyte infiltration in the colon of DSS-induced colitis mice, accompanied by the expansion of DP Tr1 cells. The suppressive effect of intestinal CD4+ T cells in HK-C60-treated mice was IL-10-dependent, as demonstrated by an in vitro IL-10 neutralizing assay. Thus, C60-based probiotics promote the creation of an anti-inflammatory intestinal environment by increasing IL-10+ Tr1 cells rather than Tregs.

immunology↗

bioRxiv2024

Lactococcus lactis subsp. cremoris C60 promotes immunoglobulin A production from B cells through functional modification of dendritic cells in intestinal environment

Probiotics utilizing lactic acid bacteria (LAB) have gained considerable attention in recent trends promoting self-managed health. Specifically, LAB-mediated immune modulation has been a key focus due to its potential to reduce the risk of pathogenic invasion and enhance host immunity. Immunoglobulin A (IgA) plays a crucial role in innate defense against various pathogens. Although only a limited number of probiotic LAB strains have been shown to increase IgA production, this capability remains of great interest. Here, we report a new strain, Lactococcus lactis subsp. cremoris C60 (C60), which promotes IgA production through functional modulation of intestinal B cells and dendritic cells (DCs). Heat-killed (HK)-C60 increased both pro-inflammatory and anti-inflammatory cytokine productions in DCs via the Toll-like receptor (TLR)-Myeloid differentiation primary response 88 (MyD88) signaling pathway, as demonstrated in both a physiological mouse model and in vitro cultures using bone marrow-derived dendritic cells (BMDCs). Notably, intragastric administration of HK-C60 significantly increased systemic IgA production, which was associated with the functional modification of B cells in the Peyers patches (PPs) of the small intestine. Immunophenotyping of PP cells from HK-C60-administered mice revealed both an expansion and functional upregulation of B cells. Mechanistically, we identified that DC-derived interleukin-6 (IL-6) and IL-10 play essential roles in the C60-mediated increase in IgA production by B cells. Finally, we evaluated the effect of C60 on IgA production using human peripheral blood mononuclear cells (PBMCs). Consistent with our findings in the mouse model, PBMCs produced IgA upon HK-C60 stimulation in an IL-6- and IL-10-dependent manner. Our results suggest that C60 is a novel probiotic strain capable of promoting intestinal immune homeostasis by upregulating IgA production, underscoring its potential for probiotic applications focused on immune conditioning.

immunology↗