Annu Rev Immunol

Annu Rev Immunol. which recognizes stress-induced ligands, activating KIRs lacking inhibitory motifs, and the Natural Cytotoxicity Receptor Family (NKp46, NKp30, NKp44), which directly recognize viral or cellular antigens (11, 13, 14, 22C25). In contrast, NK lysis through the indirect pathway of killing utilizes the Fc-gamma-RIII (CD16) activating receptor to mediate antigen-dependent NK cytotoxicity (ADCC) in the presence of antibodies specific for viral surface proteins on target cells (16, 26, 27). Additional signals from NK adapter proteins such as 2B4 (23, 28C32) and CD2 (33, 34) may further increase ADCC activity by serving as co-stimulatory signals in synergy with CD16. Cytokines such as IL-2, IL-12, IL-15, IL-21 and Type-I Interferons (IFN-, ) provided by accessory cells further augment NK lysis of virally infected target cells through both the direct and indirect pathways of cytotoxicity (35C37). While defects in the direct and indirect pathways of NK cytotoxicity have been well documented during viremia in Benzyl benzoate People Living With HIV (PLWH), NK cytotoxic function has been shown to be largely restored following suppression of viremia during prolonged anti-retroviral therapy (ART) (38C43). Once NK cells mediate cytotoxicity against a target cell, they retain potential to mediate degranulation against additional targets (44) and differentiate into mature NK cells bearing Benzyl benzoate the CD57 maturation marker over time (45, 46). In contrast to T cells where CD57 is Mmp2 expressed upon senescence, the CD57 maturation marker is expressed on a subset of NK cells (typically 40C80% of CD56dim NK cells) that correlates with Benzyl benzoate age and the diversity of the NK repertoire (45, 46). NK cells expressing CD57 have been shown to possess higher NK cytokine production (47) and enhanced ADCC potential (45). In PLWH however, the role of CD57 in marking a specialized NK ADCC effector subset is often confounded by the increased presence of the NKG2C receptor (48, 49). Following acute viremia or viral reactivation by Cytomegalovirus (CMV), a large increase NKG2C positive (NKG2Cpos) NK cells arises in approximately 50% of ART-suppressed PLWH (48, 49). CD57 is co-expressed with NKG2C on these CMV-specific adaptive NK cells due to their differentiated status, but CD57 is not directly involved in recognition of virally infected cells (50C52). Rather, NKG2C, due to its interaction with HLA-E presenting peptides from the viral UL40 protein (which mimics the leader peptides from classical MHC Class-1 proteins), represents the NK activating receptor responsible for recognition of CMV infected cells (53C56). A subset of these NKG2Cpos NK cells become deficient in the Fc signaling chain over time which allows them to mediate stronger ADCC signaling following utilization of the CD3 signaling chain (57C59). NKG2Cpos NK cells from CMV sero-positive individuals also possess increased levels of the CD2 co-receptor for mediating strong ADCC in conjunction with CD16 (33, 34, 60, 61). Together, these phenotypic results help to explain the strong ADCC activity of NKG2Cpos NK cells against CMV infected target cells coated with CMV-specific antibodies (62, 63). However, this observation adds uncertainty as to whether NKG2C or CD57 positive NK subset best tracks with ADCC activity among ART-suppressed PLWH. In this report, we define the phenotypic and functional role of CD57 and NKG2C positive NK cells from ART-suppressed PLWH and control donors to identify the predominant NK effector cell subset that can utilize BNAbs in the clearance of HIV-infected cell targets through ADCC. Results. Advanced Poly-chromatic Flow Cytometry Showing ADCC Receptor Expression Among NK Subsets in PLWH. In order to identify the main NK effector subset capable of facilitating Fc-mediated HIV target clearance in the presence of BNAbs, we measured the phenotypic expression Benzyl benzoate of activation markers and cytotoxicity receptors relevant to ADCC on NK cells expressing CD57 and/or NKG2C from ART-suppressed PLWH utilizing Advanced Poly-chromatic Flow Cytometry Benzyl benzoate (see Supplementary Figure 1A for gating strategy). Among the CD56dim NK subset, we identified a dramatic difference between CD57pos and CD57neg NK cells from ART-suppressed PLWH at the population level by bh-SNE analysis (Figure 1A). In contrast, no clear delineation was observed between NKG2Cpos and.

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