Immunological properties of dendritic cells in HIV-1 infection

Detta är en avhandling från Stockholm : Karolinska Institutet, Department of Medicine at Huddinge University Hospital

Sammanfattning: Dendritic cells (DCs) capture antigens for intracellular processing to form MHC-peptide complexes involved in the generation of antigen specific T cell responses. After encountering microbes, DCs migrate from the periphery to the regional lymph nodes. This leads to their maturation and results in increased cell surface expression of MHC and co- stimulatory molecules. At this stage, DCs also express cytokines and chemokines that direct the antigen specific T helper cells to Th1 or Th2 type of responses. DCs may regulate biological activities important for HIV-1 pathogenesis. They can be the initial target cells in HIV- 1 transmission in the mucosa due to their expression of CD4 and the beta-chemokine recptors, both required for viral entry. HIV-1 may also be entrapped on the cell surface of DCs through binding to the DC-SIGN receptor. Thus, DCs carrying HIV-1 during migration to the lymphoid tissue (LT) may contribute to the dissemination of the virus to adjacent CD4+ T cells. In addition, HIV-1 targeted DCs may also exhibit impaired antigen presenting capacity resulting in inadequate anti-HIV-1 specific T cell responses. In order to explore if HIV- 1 exerted any effect on their cytokine producing capacity and maturation we first developed an in vitro stimulation model for DCs. Intracellular detection of cytokines (IL- 1 ra/alpha/beta, TN17-alpha, IL-6, IL10, IL- 12, GM-CSF) and chemokines (RANTES, MIP- 1 alpha/beta IL-8) at the single cell level indicated that all subtypes of DCs predominantly produced the IL-1 cytokines in response to LPS stimulation. LPS stimulation of HIV-1 exposed DCs resulted in increased expression of IL- 1beta and TNF-alpha and decreased IL-1ra compared to uninfected LPS stimulated DCs. This elevated pro-inflammatory activity in DCs may contribute to enhanced replication of HIV-1 in bystander T cells. Despite that numerous DCs expressed HIV-1 DNA after HIV-1 exposure in vitro, no detectable alteration of expression of co-stimulatory molecules was identified. We next characterized the phenotype of DCs and related cytokine expression in vivo in LT from individuals at different stages of HIV-1 infection. The acute phase of infection was characterised by a significant, up to 10-fold, influx of interdigitating DCs expressing CD1a, S-100b, CD83 and DC-SIGN. The co-stimulatory molecules CD80 and CD86 were however only partially upregulated without generating a complete extrafollicular network as found in acute EBV infection, despite increased IL-1ra/alpha/beta, IFN-alpha, IL-12 and CD40 expression. Increased levels of interdigitating DCs with low expression of CD80 and CD86 persisted in asymptomatic chronically HIV-1 infected patients but were reduced in AIDS. This lack of complete functional co-stimulatory molecule expression may affect the expansion of HIV1 specific CD4+ T cells in vivo. Furthermore, we studied transfer of HIV-1 to DCs in vitro and subsequent ability to induce immune responses. We found that DCs readily engulfed apoptotic cells derived from a lymphoma T cell line with integrated HIV- 1 DNA. This resulted in a subsequent expression of HIV- 1 DNA and proteins in DCs. In addition, DCs co-cultured with HIV-1 containing apoptotic bodies induced proliferation of autologous PBMC while DCs exposed to a cell free HIV-1 isolate abrogated this response. We speculate that administration of HIV-1 containing apoptotic bodies may be a therapeutic vaccine strategy to reconstitute the anti-HIV-1 specific immune responses.

  HÄR KAN DU HÄMTA AVHANDLINGEN I FULLTEXT. (följ länken till nästa sida)