Article

Ubiquitination of CD86 is a key mechanism in regulating antigen presentation by dendritic cells.

Department of Microbiology and Immunology, Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA 94143, USA.
The Journal of Immunology (Impact Factor: 5.36). 08/2011; 187(6):2966-73. DOI: 10.4049/jimmunol.1101643
Source: PubMed

ABSTRACT Dendritic cells (DCs) require costimulatory molecules such as CD86 to efficiently activate T cells for the induction of adaptive immunity. DCs maintain minimal levels of CD86 expression at rest, but upregulate levels upon LPS stimulation. LPS-stimulated DCs produce the immune suppressive cytokine IL-10 that acts in an autocrine manner to regulate CD86 levels. Interestingly, the underlying molecular mechanism behind the tight control of CD86 is not completely understood. In this study, we report that CD86 is ubiquitinated in DCs via MARCH1 E3 ubiquitin ligase and that this ubiquitination plays a key role in CD86 regulation. Ubiquitination at lysine 267 played the most critical role for this regulation. CD86 is ubiquitinated in MARCH1-deficient DCs to a much lesser degree than in wild-type DCs, which also correlated with a significant increase in CD86 expression. Importantly, CD86 is continuously ubiquitinated in DCs following activation by LPS, and this was due to the autocrine IL-10 inhibition of MARCH1 downregulation. Accordingly, DCs lacking MARCH1 and DCs expressing ubiquitination-resistant mutant CD86 both failed to regulate CD86 in response to autocrine IL-10. DCs expressing ubiquitination-resistant mutant CD86 failed to control their T cell-activating abilities at rest as well as in response to autocrine IL-10. These studies suggest that ubiquitination serves as an important mechanism by which DCs control CD86 expression and regulate their Ag-presenting functions.

Download full-text

Full-text

Available from: Satoshi Ishido, Jun 28, 2015
0 Followers
 · 
98 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A large number of RING finger (RNF) proteins are present in eukaryotic cells and the majority of them are believed to act as E3 ubiquitin ligases. In humans, 49 RNF proteins are predicted to contain transmembrane domains, several of which are specifically localized to membrane compartments in the secretory and endocytic pathways, as well as to mitochondria and peroxisomes. They are thought to be molecular regulators of the organization and integrity of the functions and dynamic architecture of cellular membrane and membranous organelles. Emerging evidence has suggested that transmembrane RNF proteins control the stability, trafficking and activity of proteins that are involved in many aspects of cellular and physiological processes. This review summarizes the current knowledge of mammalian transmembrane RNF proteins, focusing on their roles and significance.
    12/2011; 1(4):354-93. DOI:10.3390/membranes1040354
  • [Show abstract] [Hide abstract]
    ABSTRACT: Human T-cell leukemia virus type I (HTLV-I), a causative agent of adult T-cell leukemia (ATL), is transmitted from mother to child, predominantly by breastfeeding. Oral HTLV-I infection and infection early in life are associated with a subsequent risk of ATL. Although the pathogenic mechanisms of ATL remain largely unknown, the host immune system seems to play an important role in HTLV-I pathogenesis. Previous studies have shown that monocytes from ATL patients had reduced capacity for dendritic cell (DC) differentiation. Therefore, we performed the present study to clarify the mechanisms responsible for the impairment of DC differentiation using HTLV-I-infected breast milk macrophages (HTLV-BrMMø). We found that when CD14⁺ monocytes were cultured with GM-CSF and IL-4 in the presence of HTLV-BrMMø, they altered the surface phenotype of immature DCs and the stimulatory capacity of T-cell proliferation. The presence of HTLV-BrMMø significantly blocked the increased expression of CD1a, CD1b, CD11b, DC-SIGN, and HLA-DR; however, increased expression of CD1d and CD86 was observed. These effects could be partially replicated by incubation with culture supernatants from HTLV-BrMMø. The impairment of monocyte differentiation might be not due to HTLV-I infection of monocytes, but might be due to unknown soluble factors. Since other HTLV-I-infected cells exhibited similar inhibitory effects on monocyte differentiation to DCs, we speculated that HTLV-I infection might cause the production of some inhibitory cytokines in infected cells. Identifying the factors responsible for the impairment of monocyte differentiation to DCs may be helpful to understand HTLV-I pathogenesis.
    Viral immunology 02/2012; 25(2):106-16. DOI:10.1089/vim.2011.0069 · 1.64 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Tissue inhibitor of metalloproteinase-3 (TIMP-3) is one of a family of proteins inhibiting matrix metalloproteinases, which has also been identified as a mediator for checking inflammation. Meanwhile, it is well known that inflammation causes the activation of the immune response. However, it is not clear whether TIMP-3 plays a role in the immune system. In the present study, we demonstrated a novel function of TIMP-3 in Th1/Th2 polarization through its influence on the antigen-presenting cells. First, TIMP-3 was found strikingly up-regulated by IL-4 during the differentiation of human dendritic cells via the p38MAPK pathway. Second, the expression of costimulatory molecule-CD86 was repressed by TIMP-3. Besides, the induction of IL-12 in matured dendritic cells was significantly inhibited in a PI3K-dependent manner. Furthermore, dendritic cells matured in the presence of TIMP-3 could stimulate allogeneic naive T helper (Th) cells to display a prominent Th2 polarization. Importantly, in an autoimmune disorder-primary immune thrombocytopenia, TIMP-3 showed a statistically positive correlation with IL-4 and platelet count, but a negative correlation with IFN-γ in patient blood samples. Collectively, these in vitro and in vivo data clearly suggested a novel role of TIMP-3 in Th1/Th2 balance in humans.
    Blood 03/2012; 119(20):4636-44. DOI:10.1182/blood-2011-08-376418 · 9.78 Impact Factor