Circulation of gut-preactivated naïve CD8⁺ T cells enhances antitumor immunity in B cell-defective mice

• Published in: Proceedings of the National Academy of Sciences - PNAS 2020-09, Vol.117 (38), p.23674-23683
• Main Authors: Akrami, Maryam, Menzies, Rosemary, Chamoto, Kenji, Miyajima, Michio, Suzuki, Ryuji, Sato, Hiroyuki, Nishii, Akiko, Tomura, Michio, Fagarasan, Sidonia, Honjo, Tasuku
• Format: Article
• Language: English
• Subjects: Activation-induced cytidine deaminase; Animals; Anticancer properties; Antigens; Antigens, Ly - immunology; Antigens, Ly - metabolism; Antitumor activity; B-Lymphocytes; Biological Sciences; Cancer immunotherapy; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cell Line, Tumor; Cells, Cultured; Cytidine deaminase; Dysbacteriosis; Dysbiosis - immunology; Gastrointestinal Microbiome - immunology; Gene deletion; Germfree; Heterogeneity; Immunity; Immunoglobulin A - immunology; Immunoglobulin A - metabolism; Immunotherapy; Interferon; Interferon Type I - immunology; Interferon Type I - metabolism; Intestinal microflora; Lymph nodes; Lymph Nodes - cytology; Lymphocytes; Lymphocytes T; Membrane Proteins - immunology; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Microbiomes; Microorganisms; Mitochondria; Mucosa; Neoplasms, Experimental - immunology; Signal Transduction - immunology; Stem cells; Subpopulations
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2010981117

The gut microbiome has garnered attention as an effective target to boost immunity and improve cancer immunotherapy. We found that B cell-defective (BCD) mice, such as μ-membrane targeted deletion (μMT) and activation-induced cytidine deaminase (AID) knockouts (KOs), have elevated antitumor immunity under specific pathogen-free but not germ-free conditions. Microbial dysbiosis in these BCD mice enriched the type I IFN (IFN) signature in mucosal CD8⁺ T cells, resulting in up-regulation of the type I IFN-inducible protein stem cell antigen-1 (Sca-1). Among CD8⁺ T cells, naïve cells predominantly circulate from the gut to the periphery, and those that had migrated from the mesenteric lymph nodes (mLNs) to the periphery had significantly higher expression of Sca-1. The guteducated Sca-1⁺ naïve subset is endowed with enhanced mitochondrial activity and antitumor effector potential. The heterogeneity and functional versatility of the systemic naïve CD8⁺ T cell compartment was revealed by single-cell analysis and functional assays of CD8⁺ T cell subpopulations. These results indicate one of the potential mechanisms through which microbial dysbiosis regulates antitumor immunity.