Manipulation of immune cell functions, independently of direct infection of these cells, emerges as a key process in viral pathophysiology. Chronic infection by Human T-cell Leukemia Virus type 1 (HTLV-1) is associated with immune dysfunctions, including misdirected responses of dendritic cells (DCs). Here, we interrogate the ability of transformed HTLV-1-infected T cells to manipulate human DC functions. We show that exposure to transformed HTLV-1-infected T cells induces a biased and peculiar transcriptional signature in monocyte-derived DCs, associated with an inefficient maturation and a poor responsiveness to subsequent stimulation by a TLR4 agonist. This poor responsiveness is also associated with a unique transcriptional landscape characterized by a set of genes whose expression is either conferred, impaired or abolished by HTLV-1 pre-exposure. Induction of this functional impairment requires several hours of coculture with transformed HTLV-1-infected cells, and associated mechanisms driven by viral capture, cell-cell contacts, and soluble mediators. Altogether, this cross-talk between infected T cells and DCs illustrate how HTLV-1 might co-opt communications between cells to induce a unique local tolerogenic immune microenvironment suitable for its own persistence.
Copyright: © 2024 Carcone et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Protective immunity to dengue virus (DENV) requires antibody response to all four serotypes. Systems vaccinology identifies a multi-OMICs pre-vaccination signature and mechanisms predictive of broad antibody responses after immunization with a tetravalent live attenuated DENV vaccine candidate (Butantan-DV/TV003). Anti-inflammatory pathways, including TGF-β signaling expressed by CD68low monocytes, and the metabolites phosphatidylcholine (PC) and phosphatidylethanolamine (PE) positively correlate with broadly neutralizing antibody responses against DENV. In contrast, expression of pro-inflammatory pathways and cytokines (IFN and IL-1) in CD68hi monocytes and primary and secondary bile acids negatively correlates with broad DENV-specific antibody responses. Induction of TGF-β and IFNs is done respectively by PC/PE and bile acids in CD68low and CD68hi monocytes. The inhibition of viral sensing by PC/PE-induced TGF-β is confirmed in vitro. Our studies show that the balance between metabolites and the pro- or anti-inflammatory state of innate immune cells drives broad and protective B cell response to a live attenuated dengue vaccine.
Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

Abstract Manipulation of immune cell functions, independently of direct infection of these cells, emerges as a key process in viral pathophysiology. Chronic infection by Human T-cell Leukemia Virus type 1 (HTLV-1) is associated with immune dysfunctions, including misdirected responses of dendritic cells (DCs). Here, we interrogate the ability of HTLV-1-infected T cells to indirectly manipulate human DC functions. We show that upon coculture with chronically infected T cells, monocyte-derived DCs (MDDCs) fail to fully mature. We further show that exposure to HTLV-1-infected T cells induces a unique transcriptional signature in MDDCs, which differs from a typical maturation program, and which is correlated with a dampened ability of HTLV-1-exposed MDDCs to subsequently respond to restimulation. Induction of this tolerogenic behavior is not strictly dependent on capture of HTLV-1 viral particles by MDDCs, nor on cell-cell contacts between HTLV-1-infected T cells and MDDCs, but is instead the result of a molecular dialogue between HTLV-1-infected T cells and MDDCs upon coculture, illustrating how HTLV-1 might indirectly induce a local tolerogenic immune microenvironment suitable for its own persistence.

Manipulation of immune cell functions, independently of direct infection of these cells, emerges as a key process in viral pathophysiology. Chronic infection by Human T-cell Leukemia Virus type 1 (HTLV-1) is associated with immune dysfunctions, including misdirected responses of dendritic cells (DCs). Here, we interrogate the ability of transformed HTLV-1-infected T cells to manipulate human DC functions. We show that exposure to transformed HTLV-1-infected T cells induces a biased and peculiar transcriptional signature in monocyte-derived DCs, associated with an inefficient maturation and a poor responsiveness to subsequent stimulation by a TLR4 agonist. This poor responsiveness is also associated with a unique transcriptional landscape characterized by a set of genes whose expression is either conferred, impaired or abolished by HTLV-1 pre-exposure. Induction of this functional impairment requires several hours of coculture with transformed HTLV-1-infected cells, and associated mechanisms driven by viral capture, cell-cell contacts, and soluble mediators. Altogether, this cross-talk between infected T cells and DCs illustrate how HTLV-1 might co-opt communications between cells to induce a unique local tolerogenic immune microenvironment suitable for its own persistence. Significance Chronic viral infection is associated with an escape from immune surveillance. This may rely on the induction of inappropriate DC responses, which can contribute to immunopathology. Immune dysfunctions have been repeatedly reported in people living with Human T-cell Leukemia Virus type 1 (HTLV-1), years before fatal clinical symptom onset, including misdirected responses of dendritic cells (DCs). Here, we report that HTLV-1-infected T cells actively manipulate neighboring, uninfected MDDC functions by rewiring their transcriptional response, leading to a biased, pro-tolerogenic responsiveness in MDDCs, induced by the bidirectional release of soluble mediators, in cooperation with mechanisms dependent on cell-cell contacts. This cross-talk illustrate how HTLV-1 might co-opt communications between cells to induce a local tolerogenic immune microenvironment suitable for its own persistence

Macrophages play an important role in the suppression and activation of immune anti-cancer response, but little is known about dominant macrophage phenotype in the lung cancer environment, evaluated by bronchoalveolar lavage fluid (BALF). The aim of this study was to characterize macrophages in BALF from a lung affected by cancer (cBALF) and a healthy lung (hBALF) of the same patient regarding their individual macrophage polarization and selected cytokines profile. A total of 36 patients with confirmed lung cancer were investigated. Macrophages markers: CD206 CD163 CD80 CD86 CD40 CD45, Arginase-1, and CD68 were evaluated by flow cytometry. Cytokines (IL-1 RA, IL-6, IL-10, TNF-α, IL-1β, IL-12, IL-23, and TGF-β) profile was analyzed. There was higher median proportion of macrophages in Cbalf than in Hbalf. The population of macrophages presented immunophenotype: Ccd68+bright CD206+bright CD163+bright CD80+ CD86+ CD40+bright CD45+ cArginase+. We observed some trends in the expression of the analyzed antigens in clBALF and hlBLAF. The highest concentrations of IL-1RA and IL-6 were in Cbalf and Hbalf supernatant. There were the correlations between pro- and anti-inflammatory cytokines. The findings showed that macrophages include a diverse and plastic group with the presence of different antigens and cytokines, and determining the target phenotype is a complex and variable process.