An NK Cell Population Lacking FcRγ Is Expanded in Chronically Infected HIV Patients

Abstract

We previously demonstrated that NK cells from HIV-infected individuals have elevated expression of activation markers, spontaneously degranulate ex vivo, and decrease expression of a signal-transducing protein for NK-activating receptors, FcRγ. Importantly, these changes were maintained in virologically suppressed (VS) individuals receiving combination antiretroviral therapy (cART). In this study, we show that loss of FcRγ is caused by the expansion of a novel subset of FcRγ−CD56dim NK cells with an altered activation receptor repertoire and biological properties. In a cross-sectional study, FcRγ− NK cells as a proportion of total CD56dim NK cells increased in cART-naive viremic HIV-infected individuals (median [interquartile range] = 25.9 [12.6–56.1] compared with 3.80 [1.15–11.5] for HIV− controls, p < 0.0001) and in VS HIV-infected individuals (22.7 [13.1–56.2] compared with 3.80 [1.15–11.5], p = 0.0004), with no difference between cART-naive and VS patients (p = 0.93). FcRγ− NK cells expressed no NKp30 or NKp46. They showed greater Ab-dependent cellular cytotoxicity activity against rituximab-opsonized Raji cells and in a whole-blood assay measuring NK responses to overlapping HIV peptides, despite having reduced CD16 expression compared with conventional NK cells. Their prevalence correlated with CMV Ab titers in HIV− subjects but not in HIV+ individuals, and with the inflammatory marker CXCL10 in both groups. The expansion of a subset of NK cells that lacks NKp30 and NKp46 to ∼90% of CD56dim NK cells in some VS HIV+ individuals may influence NK-mediated immunosurveillance in patients receiving cART.

Natural killer cells in HIV-1 infection and therapy

“…An additional NK cell subset lacking the aNKR FcRy is expanded in chronically HIV-1 infected individuals. Similar to what it has been observed with HCMV-induced NK cells, this latter population expresses low levels of NKp30 and is endowed with remarkably high ADCC activity [47]. Taken together, these data indicate that NK cells from HIV and HCMV co-infected patients have unique immunologic features that can be potentially targeted for developing anti-viral therapeutic approaches.…”

Memory responses of natural killer cells

“…FcεRIγ- NK cells expanded robustly in vitro when co-cultured with infected cells and plasma containing virus-specific antibodies against both HCMV and influenza [88]. Notably, the frequency of FcεRIγ- NK cells was increased in HIV + individuals and was correlated with HCMV-specific antibody titers in HIV − individuals [89]. Further mechanistic studies are required to address the underlying pathways promoting the generation and expansion of FcsRIγ- NK cells, and whether there is a clinical relevance for these cells in the context of HCMV infection.…”

Antibody functional assays as measures of Fc receptor-mediated immunity to HIV - new technologies and their impact on the HIV vaccine field.

“…Mechanistically this increased activity has been linked to a switch from FcγRIIIa association with FcRγ/CD3-ζ to CD3-ζ alone by loss of FcRγ expression and synergistic signalling from CD2 which acts as a co-receptor for FcγRIIIa (reviewed in [113]). This population of "ADCC-specialised" NK cells has also been identified in viremic and cARTtreated HIV infected patients where it is expanded to comprise 90% of the mature NK compartment [112].…”

“…FcγRIIIa is the most abundant FcγR on NK cells which are major mediators of ADCC [16] and signals via the signal transduction subunits FcRγ and/or CD3-ζ [13]. Recent studies of HCMV infection have identified the expansion of adaptive NK cells with altered expression of Syk [111] and down regulation of FcγRIIIa, but which are more potent ADCC effectors and producers of IFNγ [112]. Mechanistically this increased activity has been linked to a switch from FcγRIIIa association with FcRγ/CD3-ζ to CD3-ζ alone by loss of FcRγ expression and synergistic signalling from CD2 which acts as a co-receptor for FcγRIIIa (reviewed in [113]).…”