Histone Deacetylase Inhibitors Enhance CD4 T Cell Susceptibility to NK Cell Killing but Reduce NK Cell Function

PLoS Pathogens

Bent Jakobsen¹  Paul Klenerman¹  John Frater²  CHERUB Investigators³  James Williams⁴  Julie Fox⁴  Sarah Fidler⁵  Andrew B. Gerry⁶  Matthew Pace⁶  Ayako Kurioka⁶  Nneka Nwokolo⁶ 

[1] Adaptimmune Ltd, Oxfordshire, United Kingdom;Chelsea and Westminster Hospital, London, United Kingdom;Department of Genitourinary Medicine and Infectious Disease, Guys and St Thomas' NHS Trust, London, United Kingdom;Institute for Emerging Infections, The Oxford Martin School, Oxford, United Kingdom;Oxford National Institute of Health Research Biomedical Research Centre, Oxford, United Kingdom;Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, Oxford, United Kingdom

关键词: NK cells;    T helper cells;    HIV-1;    Cell staining;    Cell degranulation;    Antiretroviral therapy;    Cytotoxic T cells;    T cells;   

DOI  :  10.1371/journal.ppat.1005782

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

In the search for a cure for HIV-1 infection, histone deacetylase inhibitors (HDACi) are being investigated as activators of latently infected CD4 T cells to promote their targeting by cytotoxic T-lymphocytes (CTL). However, HDACi may also inhibit CTL function, suggesting different immunotherapy approaches may need to be explored. Here, we study the impact of different HDACi on both Natural Killer (NK) and CTL targeting of HIV-1 infected cells. We found HDACi down-regulated HLA class I expression independently of HIV-1 Nef which, without significantly compromising CTL function, led to enhanced targeting by NK cells. HDACi-treated HIV-1-infected CD4 T cells were also more effectively cleared than untreated controls during NK co-culture. However, HDACi impaired NK function, reducing degranulation and killing capacity. Depending on the HDACi and dose, this impairment could counteract the benefit gained by treating infected target cells. These data suggest that following HDACi-induced HLA class I down-regulation NK cells kill HIV-1-infected cells, although HDACi-mediated NK cell inhibition may negate this effect. Our data emphasize the importance of studying the effects of potential interventions on both targets and effectors.

【 授权许可】

CC BY