ABSTRACT
OM-85 is a bacterial lysate used in clinical practice to reduce duration and frequency of recurrent respiratory tract infections. Whereas knowledge of its regulatory effects in vivo has substantially advanced, the mechanisms of OM-85 sensing remain inadequately addressed. Here, we show that the immune response to OM-85 in the mouse is largely mediated by myeloid immune cells through Toll-like receptor (TLR) 4 in vitro and in vivo. Instead, in human immune cells, TLR2 and TLR4 orchestrate the response to OM-85, which binds to both receptors as shown by surface plasmon resonance assay. Ribonucleic acid-sequencing analyses of human monocyte-derived dendritic cells reveal that OM-85 triggers a pro-inflammatory signature and a unique gene set, which is not induced by canonical agonists of TLR2 or TLR4 and comprises tolerogenic genes. A largely overlapping TLR2/4-dependent gene signature was observed in individual subsets of primary human airway myeloid cells, highlighting the robust effects of OM-85. Collectively, our results suggest caution should be taken when relating murine studies on bacterial lysates to humans. Furthermore, our data shed light on how a standardized bacterial lysate shapes the response through TLR2 and TLR4, which are crucial for immune response, trained immunity, and tolerance.
Subject(s)
Immunomodulation , Myeloid Cells , Toll-Like Receptor 2 , Toll-Like Receptor 4 , Humans , Toll-Like Receptor 2/metabolism , Toll-Like Receptor 2/genetics , Mice , Animals , Toll-Like Receptor 4/metabolism , Toll-Like Receptor 4/genetics , Myeloid Cells/immunology , Myeloid Cells/metabolism , Dendritic Cells/immunology , Transcriptome , Cells, Cultured , Mice, Knockout , Gene Expression Regulation , Bacterial LysatesABSTRACT
Anticancer T cells acquire a dysfunctional state characterized by poor effector function and expression of inhibitory receptors, such as PD-1. Blockade of PD-1 leads to T cell reinvigoration and is increasingly applied as an effective anticancer treatment. Recent work challenged the commonly held view that the phosphatase PTPN11 (known as SHP-2) is essential for PD-1 signaling in T cells, suggesting functional redundancy with the homologous phosphatase PTPN6 (SHP-1). Therefore, we investigated the effect of concomitant Ptpn6 and Ptpn11 deletion in T cells on their ability to mount antitumour responses. In vivo data show that neither sustained nor acute Ptpn6/11 deletion improves T cell-mediated tumor control. Sustained loss of Ptpn6/11 also impairs the therapeutic effects of anti-PD1 treatment. In vitro results show that Ptpn6/11-deleted CD8+ T cells exhibit impaired expansion due to a survival defect and proteomics analyses reveal substantial alterations, including in apoptosis-related pathways. These data indicate that concomitant ablation of Ptpn6/11 in polyclonal T cells fails to improve their anticancer properties, implying that caution shall be taken when considering their inhibition for immunotherapeutic approaches.
Subject(s)
CD8-Positive T-Lymphocytes , Programmed Cell Death 1 Receptor , CD8-Positive T-Lymphocytes/metabolism , Protein Tyrosine Phosphatase, Non-Receptor Type 6/genetics , Protein Tyrosine Phosphatase, Non-Receptor Type 6/metabolism , Signal TransductionABSTRACT
Alterations in the Regulatory factor X 7 (RFX7) gene have recurrently been reported in lymphoid cancers. Uncharacterized until recently, this transcription factor regulates genes important for ciliogenesis and for limiting cellular metabolic activity. Here we discuss these observations and conjecture on the links between the reported functions of RFX7 and its potential role in lymphoid cancers, encouraging future studies in these directions.
