Blood Myeloid Dendritic Cells from HIV-1-Infected Individuals Display a Proapoptotic Profile Characterized by Decreased Bcl-2 Levels and by Caspase-3⁺Frequencies That Are Associated with Levels of Plasma Viremia and T Cell Activation in an Exploratory Study

Abstract

Reduced frequencies of myeloid and plasmacytoid dendritic cell (DC) subsets (mDCs and pDCs, respectively) have been observed in the peripheral blood of HIV-1-infected individuals throughout the course of disease. Accumulation of DCs in lymph nodes (LNs) may partly account for the decreased numbers observed in blood, but increased DC death may also be a contributing factor. We used multiparameter flow cytometry to evaluate pro-and antiapoptotic markers in blood mDCs and pDCs from untreated HIV-1-infected donors, from a subset of infected donors before and after receiving antiretroviral therapy (ART), and from uninfected control donors. Blood mDCs, but not pDCs, from untreated HIV-1-infected donors expressed lower levels of antiapoptotic Bcl-2 than DCs from uninfected donors. A subset of HIV-1-infected donors had elevated frequencies of proapoptotic caspase-3 ؉ blood mDCs, and positive correlations were observed between caspase-3 ؉ mDC frequencies and plasma viral load and CD8 ؉ T-cell activation levels. Caspase-3 ؉ mDC frequencies, but not mDC Bcl-2 expression, were reduced with viral suppression on ART. Apoptosis markers on DCs in blood and LN samples from a cohort of untreated, HIV-1-infected donors with chronic disease were also evaluated. LN mDCs displayed higher levels of Bcl-2 and lower caspase-3 ؉ frequencies than did matched blood mDCs. Conversely, LN pDCs expressed lower Bcl-2 levels than their blood counterparts. In summary, blood mDCs from untreated HIV-1-infected subjects displayed a proapoptotic profile that was partially reversed with viral suppression, suggesting that DC death may be a factor contributing to blood DC depletion in the setting of chronic, untreated HIV disease.Dendritic cells (DCs) are antigen-presenting cells (APCs) found throughout the body that are central in bridging innate and adaptive immune responses (5, 6). Immature DCs typically detect the presence of microbes through the binding of conserved molecular patterns to pattern recognition receptors (PRRs) such as C-type lectins and Toll-like receptors (TLRs) (32, 55). DCs exposed to microbial products then undergo a regulated maturation process, migrate to lymph nodes (LNs) and stimulate naive T cells and other immune cells to induce appropriate adaptive immune responses (5, 6). Although shown to be the most potent of the APCs in activating naive T cells, DCs have also recently been shown to play a crucial role in reactivating memory T cells (43,95,99) and in maintaining peripheral tolerance to self-antigens (91, 92).Human DCs can be divided into myeloid DC (mDC) and plasmacytoid DC (pDC) subsets that differ in ontogeny, phenotype, and function (19, 50, 51, 53, 54, 61, 77-79, 87, 94). Specifically, pDCs are considered to be involved in antiviral immunity, are capable of sensing viral single-stranded RNA (ssRNA) through TLR7 and bacterial CpG DNA through TLR9, and predominantly produce type I interferons (IFNs). Conversely, mDCs sense both bacterial and viral pattern motifs through a broader range of TLRs (TLR1 to TLR8) and are in...

Shift in Monocyte Apoptosis with Increasing Viral Load and Change in Apoptosis-Related ISG/Bcl2 Family Gene Expression in Chronically HIV-1-Infected Subjects

“…6), supporting specific candidate roles of these genes as determinants of monocyte apoptosis in HIV-infected subjects. The impact of HIV-1 on Bcl2-mediated apoptosis in the CD4 compartment is also well described (reviewed in reference 39), and the effect on non-CD4 cell types, namely, CD8 T cells (71), dendritic cells (72), and now monocytes, suggests a global impact of HIV-1 viremia and immune activation on Bcl2-mediated apoptosis regulation. In addition, it has been established that Rb1 can override p53-mediated apoptosis induction in vitro (50), yet it remains to be determined whether Bax and ISG12 family expression can override antiapoptotic Rb1 expression as suggested by our data.…”

Sensitization with vaccinia virus encoding H5N1 hemagglutinin restores immune potential against H5N1 influenza virus

“…However, one possible mechanism is that infection of immune-competent dendritic cells (or other accessory cells) with H5N1 HPAI virus might directly deplete dendritic cells in the parafollicular region32. Alternatively, virus-infected cells may exhibit altered surface expression of FAS, CD40, CD80, CD86, and/or anti-apoptotic molecules such as intracellular Bcl-2363738. Under those circumstances, apoptosis of dendritic cells might be induced by the virus-infected cells.…”

Differential Interleukin-10 (IL-10) and IL-23 Production by Human Blood Monocytes and Dendritic Cells in Response to Commensal Enteric Bacteria

“…Quality control on the LSR-II was performed daily through the Cytometer Setup and Tracking component of the BD FACSDiva software (BD Biosciences), as previously described (10). A median of 401987.5 total events (range, 67,589 to 896308 total events) was collected from FACS experiments.…”