NKG2C ⁺ NK Cells Are Enriched in AIDS Patients with Advanced-Stage Kaposi's Sarcoma

Abstract

Kaposi's sarcoma (KS) is an AIDS-defining condition in individuals withRecognition of infected target cells by NK cells is regulated by receptors for major histocompatibility complex class I (MHC-I) and pathogen-derived molecules (3,14). Killer cell immunoglobulin-like receptor (KIR) family members, which are expressed on NK cells, influence the risk of progression to AIDS in combination with HLA-B alleles (15, 16). However, the proportion of NK cells expressing inhibitory KIR increases and those expressing activating natural cytotoxicity receptors (NCR) are less abundant in PWHA (1,5,6,17).We have shown that NK cells from PWHA are enriched for a subset bearing the C-type, lectin-like receptor NKG2C (20). The NKG2C receptor mediates NK cell responses to a limited set of ligands in association with HLA-E, including a human cytomegalovirus (HCMV) peptide, and to HCMV-infected fibroblasts (9, 10). However, NK cells bearing NKG2C predominantly express inhibitory KIR and have low levels of activating NCR, which may compromise their abilities to mount cytolytic responses (8,20).As NKG2C ϩ NK cells have a predominantly inhibitory phenotype, the dominance of this subset could have an impact on disease prognosis in AIDS patients, including those with KS. We used the AIDS Clinical Trial Group (ACTG) clinical staging system, which is applied to all AIDS KS patients upon diagnosis, to investigate the relationship between the NK cell phenotype and function and disease prognosis in HIV-1 infection.Patients

IL-12–producing monocytes and HLA-E control HCMV-driven NKG2C+ NK cell expansion

“…While HCMV was the first pathogen that was shown to promote the expansion of the NKG2C + NK cell subset, similar observations were made in the context of hantavirus (15) and chikungunyavirus infection (16) as well as in EBV, HBV, HCV (17)(18)(19), and HIV (20)(21)(22). Notably, in EBV, hepatitis, and HIV infection, expansion of NKG2C + NK cells was only detected when the patients were also seropositive for HCMV, and Björkström and coworkers likewise speculate that previous CMV infection might have (Figure 2, A-C).…”

“…During viral infections, such as HCMV, a remarkable expansion of an NKG2C + subset of NK cells has been described in numerous studies (8)(9)(10)(11)(15)(16)(17)(18)(19)(20)(21)(22). The molecular mechanisms driving this expansion, however, have remained largely elusive.…”

Depletion of natural killer cells in the colonic lamina propria of viraemic HIV-1-infected individuals

“…NK cells are not normally able to prevent infection by HIV-1, however, and once established, HIV-1 drives NK cell depletion in the peripheral blood and a shift in blood NK cell populations towards a functionally compromised CD56 negative NK cell population and an NKG2Cþ subset with altered NK receptor expression [4][5][6][7]. Control of plasma viraemia, using highly active antiretroviral therapy (HAART), leads to a reversal of some effects of chronic HIV-1 infection on peripheral NK cells, including repopulation and a reduction in the proportion of CD56 À NK cells in the blood [6].…”

Natural killer cell receptor expression reflects the role of human cytomegalovirus in the pathogenesis of a subset of CD4+ T-cell large granular lymphocytosis

“…Increased proportions of CD94/NKG2Cϩ cells in peripheral blood have been associated with a positive serology for HCMV in healthy individuals [7], and human immunodeficiency virus-1 (HIV-1)-infected patients [12,13]. Moreover, NKG2Cϩ NK cells were shown to expand upon co-culture of PBMC with HCMVinfected fibroblasts [14].…”