CD137 expression and signal function drive pleiotropic γδ T-cell effector functions that inhibit intracellular M. tuberculosis growth.

Co-activation signal that induces/sustains pleiotropic effector functions of antigen-specific γδ T cells remains unknown. Here, Mycobacteria tuberculosis (Mtb) tuberculin administration during tuberculosis (TB) skin test resulted in rapid expression of co-activation signal molecules CD137 and CD107a by fast-acting Vγ2Vδ2 T cells in TB-resistant subjects (Resisters), but not patients with active TB. And, anti-CD137 agonistic antibody treatment experiments showed that CD137 signaling enabled Vγ2Vδ2 T cells to produce more effector cytokines and inhibit intracellular Mtb growth in macrophages (Mɸ). Consistently, Mtb antigen (Ag) HMBPP stimulation induced sustainable high-level CD137 expression in fresh and activated Vγ2Vδ2 T cells from uninfected subjects, but not TB patients. CD137+Vγ2Vδ2 T-cell subtype predominantly displayed central memory phenotype and mounted better proliferative responses than CD137-Vγ2Vδ2 T-cells. In response to HMBPP, CD137+Vγ2Vδ2 T-cell subtype rapidly differentiated into greater numbers of pleiotropic effector cells producing anti-Mtb cytokines compared to CD137-Vγ2Vδ2 T subtype, with the non-canonical NF-κB pathway involved. CD137 expression in Vγ2Vδ2 T cells appeared to signal anti-Mtb effector functions leading to intracellular Mtb growth inhibition in Mɸ, and active TB disrupted such CD137-driven anti-Mtb effector functions. CD137+Vγ2Vδ2 T-cells subtype exhibited an epigenetic-driven high-level expression of GM-CSF and de novo production of GM-CSF critical for Vγ2Vδ2 T-cell controlling of Mtb growth in Mϕ. Concurrently, exosomes produced by CD137+Vγ2Vδ2 T cells potently inhibited intracellular mycobacterial growth. Furthermore, adoptive transfer of human CD137+Vγ2Vδ2 T cells to Mtb-infected SCID mice conferred protective immunity against Mtb infection. Thus, our data suggest that CD137 expression/signaling drives pleiotropic γδ T-cell effector functions that inhibit intracellular Mtb growth.

Molecular characterization of Listeria monocytogenes strains isolated from imported food in China from 14 countries/regions, 2003-2018.

Listeria monocytogenes (Lm) is associated with severe foodborne infections and ubiquitous in the nature. Identification of characteristics of Lm transmission through trading of food products is essential for rapidly tracking Lm sources and controlling dissemination of listeriosis. In this study, a total of 44 Lm strains were isolated from food products originating from 14 countries/regions during 2003-2018 at the Shanghai port. The genomes of these Lm strains were sequenced by high-throughput sequencing. Multilocus sequence typing (MLST) analysis showed that 43 isolates were divided into 17 sequence types (STs). The distribution of STs was decentralized, with the dominant ST2 accounting for only 18.18% of the strains. The LM63 strain did not match with any of the existing STs. Core-genome MLST (cgMLST) analysis based on 1748 core genes categorized the 44 strains into 30 cgMLST types (CTs), with CT10153 and CT7892 as the most predominant CTs. Notably, LM63 and LM67 shared the same CT in the cgMLST analysis. The phylogenetic analysis based on single-copy homologous genes revealed that the 44 Lm strains were primarily classified into two lineages. The SNP analysis also indicated that these strains were roughly divided into two clades, with strains in the first clade mainly collected earlier than those in the second clade, which were predominantly collected from 2010 onwards. The analysis using the virulence factor database (VFDB) indicated that the virulence gene inlJ was the most prevalent among these 44 strains. Notably, ddrA, msbA, and sugC were enriched in this dataset, requiring further clarification of their roles in Listeria through future studies. These results might provide a clue for understanding of the global epidemiology and surveillance of Lm and present insights for implementing effective measures to reduce or prevent Listeria contamination outbreaks in imported food products.