title: Control of human herpes virus type 8-associated diseases by NK cells.
abstract: The "natural killer" (NK) cells preferentially kill targets lacking surface major histocompatibility complex class I (MHC-I) molecule expression. NK cells recognize these targets through membrane receptors, which can trigger activating or inhibitory signals for killing. Several tumors or virus-infected cells downregulate MHC-I expression as a mechanism to evade recognition and killing by cytotoxic T lymphocytes (CTL). They, however, become targets for NK cells cytotoxic activity. NK cell activity is reduced during disease progression in human immunodeficiency virus (HIV) infection, and in individuals with AIDS-associated tumors linked with infection by the oncogenic human herpes virus type-8 (HHV8), including Kaposi's sarcoma (KS) and primary effusion lymphomas (PEL). We have demonstrated that AIDS-related KS (AIDS-KS) is characterized by an increased expression of inhibitory receptors by T lymphocytes, and that HIV-non-infected patients with KS (classic KS, C-KS) have a substantial number of NK cells bearing these same receptors. NK cells from patients with C-KS are normally equipped with cytolytic molecules including granzyme A and perforin. However, the cytotoxic activity of NK cells is reduced in patients with C-KS, AIDS-KS, or PEL patients, who are all infected by the HHV8, and this correlates with disease severity. Moreover, we have found that HHV8-infected cell lines established from PELs have a reduced surface expression of MHC-I molecules and are sensitive to the lysis mediated by NK cells. Since PEL cells express the same HHV8 latency program as KS cells, these data point to MHC-I downregulation by HHV8 as a primary immune evasion mechanism against CTL responses, further reinforced by upregulation of inhibitory receptors on T and NK cells in the setting of HIV and/or HHV8 infection. Thus, studies on killing receptor regulation and signaling in T and NK cells may shed light on the pathogenesis of HHV8-associated tumors both in HIV-infected or -noninfected patients.
authors.affiliation: Clinical Immunology, Department of Clinical Medicine, University of Rome La Sapienza, 00161 Rome, Italy. mariacaterina.sirianni@uniroma1.it
authors.forename: Maria C
authors.initials: MC
authors.lastname: Sirianni
authors.forename: Massimo
authors.initials: M
authors.lastname: Campagna
authors.forename: Donato
authors.initials: D
authors.lastname: Scaramuzzi
authors.forename: Maurizio
authors.initials: M
authors.lastname: Carbonari
authors.forename: Elena
authors.initials: E
authors.lastname: Toschi
authors.forename: Ilaria
authors.initials: I
authors.lastname: Bacigalupo
authors.forename: Paolo
authors.initials: P
authors.lastname: Monini
authors.forename: Barbara
authors.initials: B
authors.lastname: Ensoli
mesh_terms: D003602:Cytotoxicity, Immunologic; D005786:Gene Expression Regulation; D015658:HIV Infections / Q000150:complications / Q000628:therapy; D006566:Herpesviridae Infections / Q000628:therapy*; D019288:Herpesvirus 8, Human / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D007107:Immune System; D007694:Killer Cells, Natural / Q000821:virology*; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000821:virology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism
chemical_list: D015395:Histocompatibility Antigens Class I