Journal article
Characterization of serotype-specific Dengue virus T cell inhibition
The Journal of infectious diseases, Vol.232(5), pp.1228-1238
11/15/2025
DOI: 10.1093/infdis/jiaf241
PMCID: PMC12614984
PMID: 40336275
Abstract
Dengue virus (DENV) serotype -2 and -3 infections are associated with more severe disease outcomes than -1 and -4, though a biological explanation for this has not been identified.
DENV serotype effects on human T cell activation were assessed by measuring T cell receptor (TCR)-mediated IL-2 release following TCR stimulation. DENV envelope (env) proteins were expressed in Jurkat CD4+ T cell lines and regions inhibiting TCR inhibition mapped by mutagenesis. TCR-signaling pathway inhibition was characterized by total internal reflection fluorescence microscopy and immunoblot. Reverse genetics validated env mapping results.
T cell incubation with DENV-1 and -4 inhibited TCR signaling whereas DENV-2 and -3 did not. Inhibition did not require viral replication. DENV env protein expression inhibited TCR by interfering with activation of proximal TCR signaling events. Amino acids (aa's) 49 to 62 of DENV 1 env were sufficient to inhibit TCR signaling, with env aa's 55 and 66 being critical. Reverse genetics confirmed that substitution of DENV-2 and -3 aa's 55 and 66 into DENV-1 and -4 reversed TCR inhibition, and DENV-1 aa 55 and 66 introduced into DENV-2 and -3 enhanced TCR inhibition.
DENV-2 and -3 are associated with more severe clinical disease than DENV-1 and -4; however, no biological explanation for this difference has been previously identified. We found that DENV-1 and -4 viral particles and env proteins blunt T cell responses by interfering with proximal TCR signaling while DENV-2 and -3 do not, potentially explaining DENV pathogenic outcomes in primary and secondary infection.
Details
- Title: Subtitle
- Characterization of serotype-specific Dengue virus T cell inhibition
- Creators
- Jinhua Xiang - University of IowaJames H McLinden - University of IowaQing Chang - University of IowaMicaela Fosdick - University of IowaHillel Haim - University of IowaAlexander Ploss - Princeton UniversityWesley Hottel - University of IowaNirjal Bhattarai - Center for Biologics Evaluation and ResearchTomokazu Tamura - Princeton UniversityJiayu Zhang - Princeton UniversityJon C D Houtman - University of IowaJack T Stapleton - University of Iowa Department of Microbiology & Immunology, Iowa City, IA, USA
- Resource Type
- Journal article
- Publication Details
- The Journal of infectious diseases, Vol.232(5), pp.1228-1238
- DOI
- 10.1093/infdis/jiaf241
- PMID
- 40336275
- PMCID
- PMC12614984
- NLM abbreviation
- J Infect Dis
- ISSN
- 1537-6613
- eISSN
- 1537-6613
- Publisher
- OXFORD UNIV PRESS INC
- Grant note
- Department of Veterans Affairs: BX000207 VA SeqCURE program of the Department of Veterans AffairsNational Institutes of Health training: 5T32AI343 National Institutes of Health/ National Cancer Institute: P30 CA086862 Human Immunology Core, University of IowaNational Institutes of Health: R01AI170205, R01 AI107301, U19A171401 China Research Council: RRID: SCR_023422 University of Iowa Carver College of Medicine
This work was supported in part by a Merit Review Grant from the Department of Veterans Affairs (BX000207 to J. T. S.); the VA SeqCURE program of the Department of Veterans Affairs to J. T. S.; a National Institutes of Health training grant (5T32AI343 to J. T. S.), which supported M. F.; the National Institutes of Health/ National Cancer Institute under award number P30 CA086862 for use of the Human Immunology Core, University of Iowa; National Institutes of Health grant R01AI170205 to H. H.; grants from the National Institutes of Health for work in the Ploss laboratory (R01 AI107301 and U19A171401 to A.P.); and a predoctoral fellowship by the China Research Council to J. Z. Sequencing data were obtained at the Genomics Division of the Iowa Institute of Human Genetics (RRID: SCR_023422), which is supported in part by the University of Iowa Carver College of Medicine.
- Language
- English
- Electronic publication date
- 05/08/2025
- Date published
- 11/15/2025
- Academic Unit
- Microbiology and Immunology; Infectious Diseases; Epidemiology; Hygienic Laboratory - Bdc; Internal Medicine
- Record Identifier
- 9984820572202771
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