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Peculiar transcriptional reprogramming with functional impairment of dendritic cells upon exposure to transformed HTLV-1-infected cells

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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE266976 | GEO | 2024/09/05

REPOSITORIES: GEO

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Project description:Human monocyte derived dendritic cells matured via galectin-1 or LPS. Experiment Overall Design: 4 conditions with 3 replicates of each include control or intreated immature MDDCS, galectin-1 treated MDDCs, LPS treated MDDCs, and vehicle control MDDCs. (each replicate is from a distinct DONOR). Dendritic cells (DCs) are potent mediators of the immune response, and can be activated by exogenous pathogen components. Galectin-1 is a member of the conserved beta-galactoside-binding lectin family that binds galactoside residues on cell surface glycoconjugates. Galectin-1 is known to play a role in immune regulation via action on multiple immune cells. However, its effects on human DCs are unknown. In this study, we show that galectin-1 induces a phenotypic and functional maturation in human monocyte-derived DCs (MDDCs) similar to but distinct from the activity of the exogenous pathogen stimuli, LPS. Immature human MDDCs exposed to galectin-1 up-regulated cell surface markers characteristic of DC maturation (CD40, CD83, CD86, and HLA-DR), secreted high levels of IL-6 and TNF-alpha, stimulated T cell proliferation, and showed reduced endocytic capacity, similar to LPS-matured MDDCs. However, unlike LPS-matured DCs, galectin-1-treated MDDCs did not produce the Th1-polarizing cytokine IL-12. Microarray analysis revealed that in addition to modulating many of the same DC maturation genes as LPS, galectin-1 also uniquely up-regulated a significant subset of genes related to cell migration through the extracellular matrix (ECM). Indeed, compared with LPS, galectin-1-treated human MDDCs exhibited significantly better chemotactic migration through Matrigel, an in vitro ECM model. Our findings show that galectin-1 is a novel endogenous activator of human MDDCs that up-regulates a significant subset of genes distinct from those regulated by a model exogenous stimulus (LPS). One unique effect of galectin-1 is to increase DC migration through the ECM, suggesting that galectin-1 may be an important component in initiating an immune response.

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Peculiar transcriptional reprogramming with functional impairment of dendritic cells upon exposure to transformed HTLV-1-infected cells

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