Circulation of gut-preactivated naïve CD8+ T cells enhances antitumor immunity in B cell-defective mice
Menée sur un modèle murin avec lymphocytes B déficients, cette étude met en évidence un mécanisme par lequel la migration des lymphocytes T CD8+ naïfs ayant été exposés à une dysbiose intestinale augmentent l'immunité antitumorale des tissus périphériques
Accumulating evidence supports important roles for the microbiota in health and disease. The absence of IgA induces microbial dysbiosis, leading to inflammation in the gut environment. Here, we found that the strong antitumor immunity of B cell-deficient mice is due to their microbial dysbiosis, leading to activation of type I interferon (IFN) signaling in peripheral CD8+ T cells. The constant circulation of CD8+ T cells, particularly the naïve subset between the periphery and the gut, leads to the induction of a gut-educated naïve subpopulation in the periphery. Exposure to type I IFN in the gut endows this naïve subpopulation with superior effector potential. These data provide important insights into how the gut environment can shape peripheral immunity.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.Data have been deposited in the Gene Expression Omnibus repository (accession IDs GSE155632 and GSE156338).
Proceedings of the National Academy of Sciences , résumé, 2019