Characterization of human CD8 T cell responses in dengue virus-infected patients from India

• Type of Material: Article
• Authors: Anmol Chandele, Emory University; Jaturong Sewatanon, Emory University; Sivaram Gunisetty, Emory University; Mohit Singla, All India Institute of Medical Sciences; Nattawat Onlamoon, Mahidol University; Rama Akondy, Emory University; Haydn Kissick, Emory University; Kaustuv Nayak, International Center for Genetic Engineering and Biotechnology, India; Elluri Seetharami Reddy, International Center for Genetic Engineering and Biotechnology, India; Haroon Kalam, International Center for Genetic Engineering and Biotechnology, India; Dhiraj Kumar, International Center for Genetic Engineering and Biotechnology, India; Anil Verma, All India Institute of Medical Sciences; HareKrushna Panda, International Center for Genetic Engineering and Biotechnology, India; Siyu Wang, Mahidol University; Nasikarn Angkasekwinai, Mahidol University; Kovit Pattanapanyasat, Mahidol University; Kulkanya Chokephaibulkit, Mahidol University; Guruprasad R. Medigeshi, Translational Health Science and Technology Institute; Rakesh Lodha, All India Institute of Medical Sciences; Sushil Kabra, All India Institute of Medical Sciences; Rafi Ahmed, Emory University; Murali Kaja, Emory University
• Language: English
• Date: 2016-01-01
• Publisher: American Society for Microbiology
• Publication Version: Final Published Version
• Copyright Statement: © 2016 Chandele et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1128/JVI.01424-16
• Title of Journal or Parent Work: Journal of Virology
• ISSN: 0022-538X
• Volume: 90
• Issue: 24
• Start Page: 11259
• End Page: 11278
• Grant/Funding Information: This work is supported by National Institutes of Health grants AI057266 (R. Ahmed), ICIDR 1U01AI115651 (R. Ahmed), IRO1AI099385 (K. Pattanapanyasat), Indo-US Vaccine Action Program BT/MB/Indo-US/VAP/06/2013 (K. Murali-Krishna), and Department of Biotechnology BT/PR5132/MED/15/85/2012 (G. Medigeshi).
• Research Categories: Health Sciences, Immunology; Biology, Virology; Biology, Microbiology

Abstract

Epidemiological studies suggest that India has the largest number of dengue virus infection cases worldwide. However, there is minimal information about the immunological responses in these patients. CD8 T cells are important in dengue, because they have been implicated in both protection and immunopathology. Here, we provide a detailed analysis of HLA-DR- CD38+ and HLA-DR+ CD38+ effector CD8 T cell subsets in dengue patients from India and Thailand. Both CD8 T cell subsets expanded and expressed markers indicative of antigen-driven proliferation, tissue homing, and cytotoxic effector functions, with the HLADR+ CD38+ subset being the most striking in these effector qualities. The breadth of the dengue-specific CD8 T cell response was diverse, with NS3-specific cells being the most dominant. Interestingly, only a small fraction of these activated effector CD8 T cells produced gamma interferon (IFN-γ) when stimulated with dengue virus peptide pools. Transcriptomics revealed downregulation of key molecules involved in T cell receptor (TCR) signaling. Consistent with this, the majority of these CD8 T cells remained IFN-γ unresponsive even after TCR-dependent polyclonal stimulation (anti-CD3 plus anti-CD28) but produced IFN-γ by TCR-independent polyclonal stimulation (phorbol 12-myristate 13-acetate [PMA] plus ionomycin). Thus, the vast majority of these proliferating, highly differentiated effector CD8 T cells probably acquire TCR refractoriness at the time the patient is experiencing febrile illness that leads to IFN-γ unresponsiveness. Our studies open novel avenues for understanding the mechanisms that fine-tune the balance between CD8 T cell-mediated protective versus pathological effects in dengue.