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T Cell Responses in Dengue Hemorrhagic Fever: Are Cross-Reactive T Cells Suboptimal?¹

Juthathip Mongkolsapaya^3,*,, Thaneeya Duangchinda^3,*, Wanwisa Dejnirattisai^*, Sirijit Vasanawathana, Panisadee Avirutnan, Aroonroong Jairungsri, Nuanpan Khemnu, Nattaya Tangthawornchaikul, Pojchong Chotiyarnwong^*, Kanokwan Sae-Jang, Michael Koch^¶, Yvonne Jones^¶, Andrew McMichael^||, Xiaoning Xu^||, Prida Malasit^2,, and Gavin Screaton^2,*

^* Department of Immunology, Division of Medicine, Hammersmith Hospital, Imperial College, London, United Kingdom; Medical Molecular Biology Unit, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok Noi, Bangkok, Thailand; Pediatric Department, Khon Kaen Hospital, Ministry of Public Health, Khon Kaen, Thailand; Medical Biotechnology Unit, National Centre for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Patumthani, Thailand; ^¶ The Division of Structure Biology, The Wellcome Trust Centre for Human Genetic, Roosevelt Drive, Oxford, United Kingdom; and ^|| Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom

Dengue virus infection poses a growing public health and economic burden in a number of tropical and subtropical countries. Dengue circulates as a number of quasispecies, which can be divided by serology into four groups or serotypes. An interesting feature of Dengue, recognized over five decades ago, is that most severe cases that show hemorrhagic fever are not suffering from a primary infection. Instead, they are reinfected with a virus of different serotype. This observation poses considerable problems in vaccine design, and it is therefore imperative to gain a full understanding of the mechanisms underlying this immunological enhancement of disease. In this study, we examined a T cell epitope restricted by HLA-A*24, a major MHC class I allele, in Southeast Asia in a cohort of children admitted to a hospital with acute Dengue infection. The cytokine profiles and the degranulation capacity of T cells generated to this epitope are defined and compared across different viral serotypes. Cross-reactive Dengue-specific T cells seem to show suboptimal degranulation but high cytokine production, which may contribute to the development of the vascular leak characteristic of Dengue hemorrhagic fever.

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