Adaptive NKG2CCD57 Natural Killer Cell and Tim-3 Expression During Viral Infections.

Hassen Kared, Serena Martelli, Shu Wen Tan, Yannick Simoni, Meng Li Chong, Siew Hwei Yap, Evan W Newell, Sylvia L F Pender, Adeeba Kamarulzaman, Reena Rajasuriar, Anis Larbi

Journal: Frontiers in immunology 2019;9():686

PMID: 29731749

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Abstract

Repetitive stimulation by persistent pathogens such as human cytomegalovirus (HCMV) or human immunodeficiency virus (HIV) induces the differentiation of natural killer (NK) cells. This maturation pathway is characterized by the acquisition of phenotypic markers, CD2, CD57, and NKG2C, and effector functions-a process regulated by Tim-3 and orchestrated by a complex network of transcriptional factors, involving T-bet, Eomes, Zeb2, promyelocytic leukemia zinc finger protein, and Foxo3. Here, we show that persistent immune activation during chronic viral co-infections (HCMV, hepatitis C virus, and HIV) interferes with the functional phenotype of NK cells by modulating the Tim-3 pathway; a decrease in Tim-3 expression combined with the acquisition of inhibitory receptors skewed NK cells toward an exhausted and cytotoxic phenotype in an inflammatory environment during chronic HIV infection. A better understanding of the mechanisms underlying NK cell differentiation could aid the identification of new immunological targets for checkpoint blockade therapies in a manner that is relevant to chronic infection and cancer.

Address: Singapore Immunology Network (SIgN), Aging and Immunity Program, Agency for Science Technology and Research (ASTAR), Singapore, Singapore.; Singapore Immunology Network (SIgN), Aging and Immunity Program, Agency for Science Technology and Research (ASTAR), Singapore, Singapore.; Academic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.; Centre of Excellence for Research in AIDS (CERiA), University of Malaya, Kuala Lumpur, Malaysia.; Academic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.; Centre of Excellence for Research in AIDS (CERiA), University of Malaya, Kuala Lumpur, Malaysia.; Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.; Centre of Excellence for Research in AIDS (CERiA), University of Malaya, Kuala Lumpur, Malaysia.; Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.; The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia.; Singapore Immunology Network (SIgN), Aging and Immunity Program, Agency for Science Technology and Research (ASTAR), Singapore, Singapore.; Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.; School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.

DOI: 10.3389/fimmu.2018.00686

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MeSH Terms: CD57 Antigens, Coinfection, Cytomegalovirus Infections, HIV Infections, Hepatitis A Virus Cellular Receptor 2, Hepatitis C, Humans, Killer Cells, Natural, NK Cell Lectin-Like Receptor Subfamily C