Lactococcus lactis subsp. cremoris C60 induces macrophages activation that enhances CD4+ T cell-based adaptive immunity

Suguru Saito; Alato Okuno; Nanae Kakizaki; Toshio Maekawa; Noriko M Tsuji

doi:10.12938/bmfh.2021-057

Lactococcus lactis subsp. cremoris C60 induces macrophages activation that enhances CD4+ T cell-based adaptive immunity

Biosci Microbiota Food Health. 2022;41(3):130-136. doi: 10.12938/bmfh.2021-057. Epub 2022 Apr 6.

Authors

Suguru Saito^{1

2

3

4}, Alato Okuno^{4

5

6}, Nanae Kakizaki⁴, Toshio Maekawa^{4

6}, Noriko M Tsuji^{4

7

8

9}

Affiliations

¹ Division of Virology, Department of Infection and Immunity, Faculty of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0431, Japan.
² Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
³ Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2R7, Canada.
⁴ Division of Cellular and Molecular Engineering, Department of Life Technology and Science, National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Higashi, Tsukuba, Ibaraki 305-8560, Japan.
⁵ Department of Health and Nutrition, Faculty of Human Design, Shibata Gakuen University, Hirosaki, Aomori 036-8530, Japan.
⁶ iFoodMed Inc., Tsuchiura, Ibaraki 300-0873, Japan.
⁷ Division of Microbiology, Department of Pathology and Microbiology, Nihon University School of Medicine, 30-1 Oyaguchi-Kamimachi, Itabashi, Tokyo 173-8610, Japan.
⁸ Division of Immune Homeostasis, Department of Pathology and Microbiology, Nihon University School of Medicine, 30-1 Oyaguchi-Kamimachi, Itabashi, Tokyo 173-8610, Japan.
⁹ Department of Food Science, Jumonji University, 2-1-28 Sugasawa, Niiza, Saitama 352-8510, Japan.

Abstract

Lactococcus lactis subsp. cremoris C60 is a probiotic strain that induces diverse functional modifications in immune cells. In this report, as a novel effect of C60 on myeloid lineage cells, we show that C60 enhances the immunological function of macrophages that consequently promotes CD4+ T cell activity in an antigen-dependent manner. Heat-killed (HK) C60 induced the production of pro-inflammatory cytokines in thioglycolate-elicited peritoneal macrophages (TPMs) much stronger than Toll-like receptor (TLR) ligand stimulation. The HK-C60 treatment also augmented the expression of antigen-presenting and co-stimulatory molecules, such as major histocompatibility complex (MHC) class II, CD80, and CD86, as well as antigen uptake in TPMs. These HK-C60-mediated functional upregulations in TPMs resulted in the promotion of CD4+ T cell activation in an antigen-dependent manner. Interestingly, the TPMs that originated from the mice fed the HK-C60 diet showed pre-activated characteristics, which was confirmed by the upregulation of cytokine production and antigen presentation-related molecule expression under lipopolysaccharide (LPS) stimulation. Furthermore, the antigen-dependent CD4+ T cell activation was also enhanced by the TPMs. This implied that antigen presentation activity was enhanced in the TPMs that originated from the HK-C60 diet mice. Thus, C60 effectively upregulates the immunological function of macrophages that directly connects to CD4+ T cell-based adaptive immunity.

Keywords: CD4+ T cells; IFN-γ; IL-12/IL-23p40; IL-6; TNF-α; antigen presentation; lactic acid bacteria; macrophages; probiotics.