RESUMO
Expansion of natural killer (NK) cells expressing NKG2C occurs following human cytomegalovirus (HCMV) infection and is amplified by human immunodeficiency virus (HIV) co-infection. These NKG2C-expressing NK cells demonstrate enhanced CD16-dependent cytokine production and downregulate FcεRIγ and promyelocytic leukemia zinc finger protein (PLZF). Lacking NKG2C diminishes resistance to HIV infection, but whether this affects NK cell acquisition of superior antibody-dependent function is unclear. Therefore, our objective was to investigate whether HCMV-driven NK cell differentiation is impaired in NKG2Cnull HIV-infected individuals. Phenotypic (CD2, CD16, CD57, NKG2A, FcεRIγ, and PLZF expression) and functional (cytokine induction and cytotoxicity) properties were compared between HIVâ»infected NKG2Cnull and NKG2C-expressing groups. Cytokine production was compared following stimulation through natural cytotoxicity receptors or through CD16. Cytotoxicity was measured by anti-CD16-redirected lysis and by classical antibody-dependent cell-mediated cytotoxicity (ADCC) against anti-class I human leukocyte antigen (HLA) antibody-coated cells. Our data indicate highly similar HCMV-driven NK cell differentiation in HIV infection with or without NKG2C. While the fraction of mature (CD57pos) NK cells expressing CD2 (p = 0.009) or co-expressing CD2 and CD16 (p = 0.03) was significantly higher in NKG2Cnull HIV-infected individuals, there were no significant differences in NKG2A, FcεRIγ, or PLZF expression. The general phenotypic and functional equivalency observed suggests NKG2C-independent routes of HCMV-driven NK cell differentiation, which may involve increased CD2 expression.
Assuntos
Infecções por Citomegalovirus/imunologia , Citomegalovirus/patogenicidade , Infecções por HIV/imunologia , Células Matadoras Naturais/virologia , Subfamília C de Receptores Semelhantes a Lectina de Células NK/genética , Adulto , Citotoxicidade Celular Dependente de Anticorpos , Diferenciação Celular , Coinfecção/imunologia , Coinfecção/virologia , Citocinas/imunologia , Feminino , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/imunologia , Humanos , Células Matadoras Naturais/citologia , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Subfamília C de Receptores Semelhantes a Lectina de Células NK/imunologia , Proteína com Dedos de Zinco da Leucemia Promielocítica/genética , Proteína com Dedos de Zinco da Leucemia Promielocítica/imunologia , Receptores de IgE/genética , Receptores de IgE/imunologia , Receptores de IgG/genética , Receptores de IgG/imunologiaRESUMO
The few initial formative studies describing non-specific and apparently spontaneous activity of natural killer (NK) cells have since multiplied into thousands of scientific reports defining their unique capacities and means of regulation. Characterization of the array of receptors that govern NK cell education and activation revealed an unexpected relationship with the major histocompatibility molecules that NK cells originally became well known for ignoring. Proceeding true to form, NK cells continue to up-end archetypal understanding of their ever-expanding capabilities. Discovery that the NK cell repertoire is extremely diverse and can be reshaped by particular viruses into unique subsets of adaptive NK cells challenges, or at least broadens, the definition of immunological memory. This review provides an overview of studies identifying adaptive NK cells, addressing the origins of NK cell memory and introducing the heretical concept of NK cells with extensive antigenic specificity. Whether these newly apparent properties reflect adaptive utilization of known NK cell attributes and receptors or a specially creative allocation from an undefined receptor array remains to be fully determined.
