Saito, S.; Okuno, A.; Kakizaki, N.; Maekawa, T.; Tsuji, N. M.

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.