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ResearchIn-Press PreviewImmunologyInfectious disease
Open Access | 10.1172/JCI169251
1Programme in Emerging Infectious Diseases, Duke-National University of Singapore Medical School, Singapore, Singapore
2Department of Paediatrics, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
3Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
Find articles by Choi, Y. in: JCI | PubMed | Google Scholar
1Programme in Emerging Infectious Diseases, Duke-National University of Singapore Medical School, Singapore, Singapore
2Department of Paediatrics, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
3Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
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Saron, W.
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1Programme in Emerging Infectious Diseases, Duke-National University of Singapore Medical School, Singapore, Singapore
2Department of Paediatrics, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
3Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
Find articles by O'Neill, A. in: JCI | PubMed | Google Scholar
1Programme in Emerging Infectious Diseases, Duke-National University of Singapore Medical School, Singapore, Singapore
2Department of Paediatrics, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
3Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
Find articles by Senanayake, M. in: JCI | PubMed | Google Scholar
1Programme in Emerging Infectious Diseases, Duke-National University of Singapore Medical School, Singapore, Singapore
2Department of Paediatrics, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
3Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
Find articles by Wilder-Smith, A. in: JCI | PubMed | Google Scholar
1Programme in Emerging Infectious Diseases, Duke-National University of Singapore Medical School, Singapore, Singapore
2Department of Paediatrics, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
3Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
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Rathore, A.
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1Programme in Emerging Infectious Diseases, Duke-National University of Singapore Medical School, Singapore, Singapore
2Department of Paediatrics, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
3Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
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St. John, A.
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Published August 1, 2024 - More info
NKT cells are innate-like T cells, recruited to the skin during viral infection, yet their contributions to long-term immune memory to viruses are unclear. We identified granzyme K, a product made by cytotoxic cells including NKT cells, is linked to induction of Th1-associated antibodies during primary dengue virus (DENV) infection in humans. We examined the role of NKT cells in vivo using DENV-infected mice lacking CD1d-dependent (CD1ddep) NKT cells. In CD1d-KO mice, Th1-polarized immunity and infection resolution were impaired, which was dependent on intrinsic NKT cell production of IFN-γ, since it was restored by adoptive transfer of WT but not IFN-γ-KO NKT cells. Furthermore, NKT cell deficiency triggered immune bias, resulting in higher levels of Th2-associated IgG1 than Th1-associated IgG2a, which failed to protect against a homologous DENV re-challenge and promoted antibody-dependent enhanced disease during secondary heterologous infections. Similarly, Th2-immunity, typified by a higher IgG4:IgG3 ratio, was associated with worsened human disease severity during secondary infections. Thus, CD1ddep NKT cells establish Th1 polarity during the early innate response to DENV, which promotes infection resolution, memory formation and long-term protection from secondary homologous and heterologous infections. These observations illustrate how early innate immune responses during primary infections can influence secondary infection outcomes.