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

Proc Natl Acad Sci U S A. 2020 Sep 22;117(38):23674-23683. doi: 10.1073/pnas.2010981117. Epub 2020 Sep 9.

Abstract

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 gut-educated 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.

Keywords: IgA; circulation between gut and periphery; gut-microbiota education; mitochondrial activation; type I IFN signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Ly / immunology
  • Antigens, Ly / metabolism
  • B-Lymphocytes
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Line, Tumor
  • Cells, Cultured
  • Dysbiosis / immunology
  • Gastrointestinal Microbiome / immunology*
  • Immunoglobulin A / immunology
  • Immunoglobulin A / metabolism
  • Interferon Type I / immunology*
  • Interferon Type I / metabolism
  • Lymph Nodes / cytology
  • Membrane Proteins / immunology
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplasms, Experimental / immunology*
  • Signal Transduction / immunology

Substances

  • Antigens, Ly
  • Immunoglobulin A
  • Interferon Type I
  • Ly6a protein, mouse
  • Membrane Proteins