Diminished IL-12 production mediates impaired T-cell stimulating capacity of lymph node dendritic cells and macrophages in SIV infection (INC9P.444)

Abstract

Abstract Mononuclear phagocytes are integral components of the innate immune system that sense invading microbes and expand antigen-specific immune responses. Thus far, their roles in progressive HIV infection remain to be clarified. We used the pathogenic simian immunodeficiency virus (SIV) rhesus macaque model to determine the immune stimulating capacity of plasmacytoid dendritic cells (pDC), myeloid DC (mDC), and macrophages (Mφ) after SIV infection, focusing on the lymph node compartment. By positive selection through live-cell sorting, we measured the ex vivo ability of each subset to respond to uridine-rich ssRNA oligos derived from the infecting strain of SIV and to subsequently drive CD4+ T cell proliferation and IFN-γ production. Isolated pDC and Mφ from infected macaques were defective at stimulating CD4+ T cells to divide and produce IFN-γ. Co-stimulatory marker upregulation on mononuclear phagocytes remained comparable in naïve and infected samples, whereas deficiencies in IFN-α and IL-12 production by pDC and Mφ were found concurrent with lower CD4+ T cell function. Furthermore, exogenous IFN-α and IL-12 supplementation was able to recover the CD4+ T cell stimulating capacity of isolated mDC and Mφ from SIV-infected lymphatic tissue. These novel findings suggest that defects in mononuclear phagocyte T cell stimulating capacity through loss of IL-12 production may contribute to the overall immune dysfunction in pathogenic SIV of rhesus macaques and HIV infection of humans.