Abstract
BackgroundHIV-1 infection is associated with profound dysfunction of myeloid dendritic cells, for reasons that remain ill-defined. Soluble HLA class I molecules can have important inhibitory effects on T cells and NK cells, but may also contribute to reduced functional properties of professional antigen-presenting cells. Here, we investigated the expression of soluble HLA class I isoforms during HIV-1 infection and assessed their functional impact on antigen-presenting characteristics of dendritic cells.ResultsSoluble HLA class I molecules were highly upregulated in progressive HIV-1 infection as determined by quantitative Western blots. This was associated with strong increases of intracellular expression of HLA class I isoforms in dendritic cells and monocytes. Using mixed lymphocyte reactions, we found that soluble HLA class I molecules effectively inhibited the antigen-presenting properties of dendritic cells, however, there was no significant influence of HLA class I molecules on the cytokine-secretion properties of these cells. The immunomodulatory effects of soluble HLA class I molecules were mediated by interactions with inhibitory myelomonocytic MHC class I receptors from the Leukocyte Immunoglobulin Like Receptor (LILR) family.ConclusionsDuring progressive HIV-1 infection, soluble HLA class I molecules can contribute to systemic immune dysfunction by inhibiting the antigen-presenting properties of myeloid dendritic cells through interactions with inhibitory myelomonocytic HLA class I receptors.
Highlights
HIV-1 infection is associated with profound dysfunction of myeloid dendritic cells, for reasons that remain ill-defined
To investigate immunoregulatory effects of soluble HLA class I isoforms in HIV-1 infection, we initially focused on quantifying the expression of HLA class I molecules in plasma and PBMC
To explore mechanisms of how soluble HLA class I isoforms can mechanistically reduce stimulatory properties of monocyte-derived dendritic cells (MDDC), we focused on their interactions with inhibitory myelomonocytic MHC class I receptors from the Leukocyte Immunoglobulin Like Receptor (LILR) family that are constitutively expressed on dendritic cells, and upregulated during chronic progressive infection [5,6]
Summary
HIV-1 infection is associated with profound dysfunction of myeloid dendritic cells, for reasons that remain ill-defined. HIV-1 infection leads to massive immune activation that results from direct stimulation of immune cells by HIV1 antigens, the release of large amounts of pro-inflammatory cytokines, and the systemic circulation of bacterial polysaccharide antigens after translocation from intestinal mucosal tissues [1] This immune activation can cause counter-regulatory activities of inhibitory components of the immune system, such as increased recruitment of regulatory T cells [2], upregulation of inhibitory receptors on antigen-specific T cells [3,4], and enhanced expression of immunoregulatory receptors on HLA class I isoforms are heterodimeric molecules that consist of a 44-kDa polymorphic glycoprotein (a chain) that is noncovalently associated with the 12-kDa nonpolymorphic b2-microglobulin. These data indicate a previously unrecognized immunoregulatory pathway that contributes to immune dysfunction of dendritic cells in HIV-1 infection
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