Abstract
Chronic HIV-infection modulates the expression of Fc gamma receptors (FcγRs) on immune cells and their antibody-dependent effector function capability. Given the increasingly recognized importance of antibody-dependent cellular cytotoxicity (ADCC) in HIV-specific immunity, we investigated the cellular distribution of FcγRIIIa on cytotoxic lymphocytes—natural killer cells and CD8+ T cells—and the effect of the FcγRIIIa-F158V variant on ADCC capacity in HIV-infected individuals (n = 23) and healthy controls (n = 23). Study participants were matched for F158V genotypes, carried two copies of the FCGR3A gene and were negative for FcγRIIb expression on NK cells. The distribution of CD56dimFcγRIIIabright and CD56negFcγRIIIabright NK cell subsets, but not FcγRIIIa surface expression, differed significantly between HIV-1 negative and HIV-1 positive donors. NK cell-mediated ADCC responses negatively correlated with the proportion of the immunoregulatory CD56brightFcγRIIIadim/neg cells and were lower in the HIV-1 positive group. Intriguingly, the FcγRIIIa-F158V variant differentially affected the NK-mediated ADCC responses for HIV-1 negative and HIV-1 positive donors. Healthy donors bearing at least one 158V allele had higher ADCC responses compared to those homozygous for the 158F allele (48.1 vs. 34.1%), whereas the opposite was observed for the HIV-infected group (26.4 vs. 34.6%), although not statistically significantly different. Furthermore, FcγRIIIa+CD8bright and FcγRIIIa+CD8dim T cell subsets were observed in both HIV-1 negative and HIV-1 positive donors, with median proportions that were significantly higher in HIV-1 positive donors compared to healthy controls (15.7 vs. 8.3%; P = 0.016 and 18.2 vs. 14.1%; P = 0.038, respectively). Using an HIV-1-specific GranToxiLux assay, we demonstrate that CD8+ T cells mediate ADCC through the delivery of granzyme B, which was overall lower compared to that of autologous NK cells. In conclusion, our findings demonstrate that in the presence of an HIV-1 infection, the cellular distribution of FcγRIIIa is altered and that the functional consequence of FcγRIIIa variant is affected. Importantly, it underscores the need to characterize FcγR expression, cellular distribution and functional consequences of FcγR genetic variants within a specific environment or disease state.
Highlights
Receptors for the Fc domain of immunoglobulin G (IgG), so called Fc gamma receptors (FcγRs), link the specificity of IgG with potent effector functions of the innate immune system
Following Fc gamma receptor gene (FCGR) genotyping, seven individuals were excluded due to the possession of an FCGR3A gene duplication (n = 1), FCGR3A gene deletion (n = 2), or gene copy number variable region 1 (CNR1) deletion that results in the expression of the inhibitory FcγRIIb on natural killer (NK) cells (n = 4)
Twenty-three human immunodeficiency virus 1 (HIV-1) positive individuals were eligible for further analysis, with the FcγRIIIaF158V genotype distribution closely resembling that observed in the general black population from the same region in South Africa [29]
Summary
Receptors for the Fc domain of immunoglobulin G (IgG), so called Fc gamma receptors (FcγRs), link the specificity of IgG with potent effector functions of the innate immune system. FcγRs comprise a family of activating (FcγRI, FcγRIIa, and FcγRIIIa) and inhibiting (FcγRIIb) receptors that are differentially expressed on innate immune cells such as natural killer (NK) cells, monocytes, dendritic cells, neutrophils, and granulocytes [1,2,3]. During an infection, these receptors play an important role in activating IgG-induced protective inflammatory processes and regulating immune responses [4,5,6,7]. ADCC responses associate with slower disease progression in HIV-1 infected adults [10,11,12,13,14]
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