title: Differential targeting of viral components by CD4+ versus CD8+ T lymphocytes in dengue virus infection.
abstract: Dengue virus (DENV) is the principal arthropod-borne viral pathogen afflicting human populations. While repertoires of antibodies to DENV have been linked to protection or enhanced infection, the role of T lymphocytes in these processes remains poorly defined. This study provides a comprehensive overview of CD4(+) and CD8(+) T cell epitope reactivities against the DENV 2 proteome in adult patients experiencing secondary DENV infection. Dengue virus-specific T cell responses directed against an overlapping 15mer peptide library spanning the DENV 2 proteome were analyzed ex vivo by enzyme-linked immunosorbent spot assay, and recognition of individual peptides was further characterized in specific T cell lines. Thirty novel T cell epitopes were identified, 9 of which are CD4(+) and 21 are CD8(+) T cell epitopes. We observe that whereas CD8(+) T cell epitopes preferentially target nonstructural proteins (NS3 and NS5), CD4(+) epitopes are skewed toward recognition of viral components that are also targeted by B lymphocytes (envelope, capsid, and NS1). Consistently, a large proportion of dengue virus-specific CD4(+) T cells have phenotypic characteristics of circulating follicular helper T cells (CXCR5 expression and production of interleukin-21 or gamma interferon), suggesting that they are interacting with B cells in vivo. This study shows that during a dengue virus infection, the protein targets of human CD4(+) and CD8(+) T cells are largely distinct, thus highlighting key differences in the immunodominance of DENV proteins for these two cell types. This has important implications for our understanding of how the two arms of the human adaptive immune system are differentially targeted and employed as part of our response to DENV infection.
authors.affiliation: Immunology Programme, Department of Microbiology, National University of Singapore, Singapore. miclr@nus.edu.sg
authors.forename: Laura
authors.initials: L
authors.lastname: Rivino
authors.forename: Emmanuelle A P
authors.initials: EA
authors.lastname: Kumaran
authors.forename: Vojislav
authors.initials: V
authors.lastname: Jovanovic
authors.forename: Karen
authors.initials: K
authors.lastname: Nadua
authors.forename: En Wei
authors.initials: EW
authors.lastname: Teo
authors.forename: Shyue Wei
authors.initials: SW
authors.lastname: Pang
authors.forename: Guo Hui
authors.initials: GH
authors.lastname: Teo
authors.forename: Victor Chih Hao
authors.initials: VC
authors.lastname: Gan
authors.forename: David C
authors.initials: DC
authors.lastname: Lye
authors.forename: Yee Sin
authors.initials: YS
authors.lastname: Leo
authors.forename: Brendon J
authors.initials: BJ
authors.lastname: Hanson
authors.forename: Kenneth G C
authors.initials: KG
authors.lastname: Smith
authors.forename: Antonio
authors.initials: A
authors.lastname: Bertoletti
authors.forename: David M
authors.initials: DM
authors.lastname: Kemeny
authors.forename: Paul A
authors.initials: PA
authors.lastname: MacAry
mesh_terms: D000328:Adult; D001402:B-Lymphocytes / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D036022:Capsid Proteins / Q000276:immunology; D002478:Cells, Cultured; D003715:Dengue / Q000276:immunology*; D003716:Dengue Virus / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007378:Interleukins / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D020543:Proteome / Q000276:immunology; D020365:RNA Helicases / Q000276:immunology; D054380:Receptors, CXCR5 / Q000096:biosynthesis; D012697:Serine Endopeptidases / Q000276:immunology; D014759:Viral Envelope Proteins / Q000276:immunology; D017361:Viral Nonstructural Proteins / Q000276:immunology; D000098546:Interleukin-21; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D036022:Capsid Proteins; D018984:Epitopes, T-Lymphocyte; D007371:Interferon-gamma; D007378:Interleukins; D020543:Proteome; D020365:RNA Helicases; D054380:Receptors, CXCR5; D012697:Serine Endopeptidases; D014759:Viral Envelope Proteins; D017361:Viral Nonstructural Proteins; D000098546:Interleukin-21; C095085:CXCR5 protein, human; C100315:NS1 protein, Flavivirus; C060028:NS3 protein, flavivirus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C096041:NS5 protein, flavivirus