Negative Regulation of Expression and Function of FcγRIII by CD3ζ in Murine NK Cells

A model of neonatal autoimmune disease has been described recently in which an epitope-specific autoantibody to murine zona pellucida 3 induces severe ovarian disease in neonatal, but not adult, mice (neonatal AOD). The autoantibody forms immune complex with endogenous ovarian zona pellucida 3, and a pathogenic CD4+ T cell response is triggered. The basis for the predominant neonatal susceptibility has not been clarified. In this study innate immunity, including neonatal NK cells, in neonatal AOD was investigated. Neonatal spleen contained readily detectable NK1.1+TCRVβ−, but not NK1.1+TCRVβ+, cells. Ab depletion of NK1.1+TCRVβ− cells inhibited neonatal AOD development. Moreover, in adoptive transfer of neonatal AOD, recipient disease was ameliorated when either donor or recipient NK cells were depleted. Thus, NK cells operate in both induction and effector phases of the disease. IFN-γ was produced by neonatal NK cells in vivo, and it may be important in neonatal AOD. Indeed, ovaries with neonatal AOD expressed high levels of IFN-γ and TNF-α which correlated with disease severity, and the disease was inhibited by IFN-γ or TNF-α Ab. Importantly, disease was enhanced by recombinant IFN-γ, and treatment of T cell donors with IFN-γ Ab also significantly reduced adoptive transfer of neonatal AOD. Finally, neonatal AOD was ameliorated in mice deficient in FcγRIII and was enhanced in FcγRIIB-deficient mice. We conclude that neonatal NK cells promote pathogenic T cell response at multiple stages during neonatal autoimmune disease pathogenesis. Also operative in neonatal AOD are other mediators of the innate system, including proinflammatory cytokines and FcγRIII signaling.

Section: Neonatal Aod Induction Is Dependent On Fc␥riiimentioning

confidence: 99%

Requirements of NK Cells and Proinflammatory Cytokines in T Cell-Dependent Neonatal Autoimmune Ovarian Disease Triggered by Immune Complex

Setiady¹,

Pramoonjago²,

Tung

2004

“…NK cells were purified from C57BL/6 or BALB/c mice as previously described (9). Briefly, splenocytes were depleted of CD4-, CD8-, and surface Ig-positive cells by magnetic cell sorting and were then stained with PE-DX5 mAb (BD PharMingen, San Diego, CA), followed by incubation with magnetic microbeads coated with anti-PE-Ab (Miltenyi Biotec, Bergisch Gladbach, Germany).…”

Section: Nk Cell Preparationmentioning

confidence: 99%

Cutting Edge: The Mouse NK Cell-Associated Antigen Recognized by DX5 Moncoclonal Antibody is CD49b (α2 Integrin, Very Late Antigen-2)

Arase

Saito

Phillips³

et al. 2001

Self Cite

211

169

DX5 mAb is a useful reagent because it stains NK cells from all mouse strains examined. We have identified the molecule recognized by DX5 mAb by using a retrovirus-mediated expression cloning system. A 5-kb cDNA encoding a protein that is reactive with the DX5 mAb was isolated from a NK cell cDNA library, and this molecule was identical with CD49b (very late Ag-2, α2 integrin). The DX5 mAb reacted with transfectants expressing CD49b, and binding of DX5 to the NK cells and CD49b transfectants was blocked in the presence of other anti-CD49b mAbs. When NK1.1+ NK cells were cultured with IL-2, they progressively lost reactivity with DX5 mAb as a consequence of cellular proliferation. Cytotoxicity mediated by the DX5+ NK cells was dramatically higher as compared with DX5− NK cells. Therefore, DX5 mAb recognizes CD49b and can be used to define functionally distinct subsets of NK cells.

“…The CD16 molecule, however, can also associate with the TCR z-chain (TCRz or CD247), a functional homolog of FcRg (17). TCRz can form heterodimers with FcRg (18); however, at least in murine NK cells, these heterodimers do not appear to associate with CD16 or act as a CD16 chaperone (19).…”

mentioning

confidence: 99%

Virologically Suppressed HIV Patients Show Activation of NK Cells and Persistent Innate Immune Activation

Lichtfuss

Cheng

Farsakoglu

et al. 2012

110

106

FcRγ is an ITAM-containing adaptor required for CD16 signaling and function in NK cells. We have previously shown that NK cells from HIV patients receiving combination antiretroviral therapy (cART) have decreased FcRγ expression, but the factors causing this are unknown. We conducted a cross-sectional study of cART-naive viremic patients (ART−), virologically suppressed patients receiving cART (ART+), and HIV-uninfected controls. CD8+ T cells were activated, as assessed by CD38+HLA-DR+ expression, in ART− patients (p < 0.0001), which was significantly reduced in ART+ patients (p = 0.0005). In contrast, CD38+HLA-DR+ NK cells were elevated in ART− patients (p = 0.0001) but did not decrease in ART+ patients (p = 0.88). NK cells from both ART− and ART+ patients showed high levels of spontaneous degranulation in ex vivo whole blood assays as well as decreased CD16 expression (p = 0.0001 and p = 0.0025, respectively), FcRγ mRNA (p < 0.0001 for both groups), FcRγ protein expression (p = 0.0016 and p < 0.0001, respectively), and CD16-dependent Syk phosphorylation (p = 0.0001 and p = 0.003, respectively). HIV-infected subjects showed alterations in NK activation, degranulation, CD16 expression and signaling, and elevated plasma markers of inflammation and macrophage activation, that is, neopterin and sCD14, which remained elevated in ART+ patients. Alterations in NK cell measures did not correlate with viral load or CD4 counts. These data show that in HIV patients who achieve viral suppression following cART, NK cell activation persists. This suggests that NK cells respond to factors different from those driving T cell activation, but which are associated with inflammation in HIV patients.