The Memory T Cell Response to West Nile Virus in Symptomatic Humans following Natural Infection Is Not Influenced by Age and Is Dominated by a Restricted Set of CD8+ T Cell Epitopes

Parsons, Robin; Lelic, Alina; Hayes, Lisa; Carter, Alexandra; Marshall, Laura; Evelegh, Carole; Drebot, Michael A.; Andonova, Maya; McMurtrey, Curtis P.; Hildebrand, William H.; Loeb, Mark; Bramson, Jonathan L.

doi:10.4049/jimmunol.181.2.1563

Cited by 27 publications

(37 citation statements)

References 38 publications

(48 reference statements)

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“…Although we could demonstrate an age-related proliferative defect of these cells in the acute phase as it has been seen also in aged mice after Listeria monocytogenes infection (54), other functional properties such as the specific CD8 + cytotoxicity and cytokine expression remain to be addressed by future studies. Interestingly, studies comparing CD8 + T cell responses in young and old individuals postinfection with West Nile flavivirus (WNV) could not find any age deficiencies in the response magnitude (55,56) and in the functional properties (57), contrasting our results, although both viruses are closely related to each other. However, in the WNV studies, specific CD8 + T cells were measured in the early memory phase, for example, 3-4 mo after onset of symptoms, whereas our data refer to specific cells in the well-defined acute response phase around day 14 after experimental infection.…”

Section: Discussioncontrasting

confidence: 56%

Low Thymic Activity and Dendritic Cell Numbers Are Associated with the Immune Response to Primary Viral Infection in Elderly Humans

Schulz

Mälzer

Domingo

et al. 2015

The Journal of Immunology

105

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Immunological competence declines progressively with age, resulting in increased susceptibility of the elderly to infection and impaired responses to vaccines. Underlying mechanisms remain largely obscure as they have been related to complex, individual systemic immune properties that are challenging to investigate. In this study, we explored age-related changes in human immunity during a primary virus infection experimentally induced by immunization with live-attenuated yellow fever (YF) vaccine. Applying detailed serology, advanced FACS analysis, and systems biology, we discovered that aged subjects developed fewer neutralizing Abs, mounted diminished YF-specific CD8+ T cell responses, and showed quantitatively and qualitatively altered YF-specific CD4+ T cell immunity. Among numerous immune signatures, low in vivo numbers of naive CD4+ recent thymic emigrants and peripheral dendritic cells correlated well with reduced acute responsiveness and altered long-term persistence of human cellular immunity to YF vaccination. Hence, we reveal in this article that essential elements of immune responses such as recent thymic emigrants and dendritic cells strongly relate to productive immunity in the elderly, providing a conceivable explanation for diminished responsiveness to vaccination with neoantigens and infection with de novo pathogens in the aged population.

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Section: Discussioncontrasting

confidence: 56%

Low Thymic Activity and Dendritic Cell Numbers Are Associated with the Immune Response to Primary Viral Infection in Elderly Humans

Schulz

Mälzer

Domingo

et al. 2015

The Journal of Immunology

105

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“…This demonstration that a large number of WNV HLA-restricted T-cell ligand sequences shared 9 or more consecutive amino acid identities with multiple other flaviviruses serves to display the full extent of potential immune cross-reactivity among (39,40) and later extended to T-cell responses (41,42). It now has been extensively studied with respect to a variety of immune responses, including thymic education, T-cell memory, pathogen virulence, and autoimmune dis- ease (43,44,45,46,47).…”

Section: Discussionmentioning

confidence: 99%

“…Several reports cite the role of CD8 ϩ cytolytic T lymphocytes (CTL) and CD4 ϩ helper T lymphocytes (HTL) in the immune response to WNV infection (3,8,42,46); however, knowledge of the identities and properties of WNV T-cell epitopes in the human host is limited, and few have been reported to date (19-21, 32, 42, 61). Thus, for this study, large-scale identification of WNV T-cell ligands was performed by use of HLA transgenic (Tg) mice, a leading animal model system for analysis of HLA-restricted T-cell responses to human pathogens (4,12,25,40,41,43,49,63,65).…”

mentioning

confidence: 99%

West Nile Virus T-Cell Ligand Sequences Shared with Other Flaviviruses: a Multitude of Variant Sequences as Potential Altered Peptide Ligands

Jung

Khan

Tan

et al. 2012

J Virol

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West Nile virus (WNV), a member of the genus Flavivirus, is a mosquito-borne RNA pathogen closely related to numerous other flaviviruses of the Japanese encephalitis (JE) group, and to a lesser degree to Dengue virus (DENV), Yellow fever virus (YFV), and several other flaviviruses of about 70 different species (5, 18). The genome is a positive-sense, single-stranded RNA of approximately 10,293 nucleotides encoding a polyprotein of approximately 3,430 amino acids (aa) that is cleaved to produce three structural proteins, capsid (C), precursor membrane (prM), and envelope (E), and seven nonstructural (NS) proteins, NS1, 2a, 2b,3, 4a, 4b, and 5 (24,37). Originally isolated in Africa in 1937 (62), WNV has become an increasingly important human pathogen widely endemic in Africa, Asia, Europe, and North America and a significant agent of viral encephalitis (28,38,45). WNV and several of the major human pathogen flaviviruses are known to cocirculate (28, 71); for example, WNV and St. Louis encephalitis virus (LEV) in North America; WNV, DENV, and Japanese encephalitis virus (JEV) around the Indian subcontinent and portions of Southeast Asia (SEA); and WNV, DENV, JEV, and Murray Valley encephalitis virus (MVE) in neighboring pockets of SEA and Australasia.The widespread colocalization of WNV with other flaviviruses calls for a greater understanding of the phylogenetic relatedness and possible pathophysiologic associations of flaviviruses. We previously reported a large-scale analysis of the conservation and variability of overlapping nonamers, the typical length of human leukocyte antigen (HLA) class I or class II binding cores of T-cell epitopes (47), of the 2,746 WNV protein sequences collected from the NCBI Entrez Protein Database (17). Notably, of the 88 completely conserved sequence fragments identified, representing 34% of the WNV proteome, 67 were also present in many other flaviviruses with identities of nine or more amino acids. These sequence homologies called attention to a broad inter-Flavivirus risk of altered peptide ligands (APL) (58), T-cell epitopes with one or more amino acid differences, that possibly would result in modified immune responses in the event of exposure to multiple Flavivirus pathogens.This study focused on analyses of the diversity and presence in

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“…+ T cells were found in the brains of JEV-and TBEV-infected mice (7,24). There are reports on human T cell responses following in vitro stimulation of PBMCs from WNV-infected patients with peptides derived from WNV Ags (25,26). They indicated a critical role of CD8 + T cells and IFN-g production in responses to a limited number of epitopes with MHC restriction.…”

Section: Cross-reaction Of Brain-infiltrating T Cells Between Wnv Andmentioning

confidence: 99%

High Clonality of Virus-Specific T Lymphocytes Defined by TCR Usage in the Brains of Mice Infected with West Nile Virus

Kitaura

Fujii

Hayasaka

et al. 2011

The Journal of Immunology

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It has been reported that brain-infiltrating T lymphocytes play critical roles in the clearance of West Nile virus (WNV) from the brains of mice. We characterized brain-infiltrating T lymphocytes by analyzing the TCR α- and β-chain repertoires, T cell clonality, and CDR3 sequences. CD3+CD8+ T cells were localized in the WNV-infected brains. The expression of CD3, CD8, CD25, CD69, perforin, and granzymes positively correlated with viral RNA levels, and high levels of expression of IFN-γ, TNF-α, and IL-2 were detected in the brains, suggesting that Th1-like cytotoxic CD8+ T cells are expanded in the brains in response to WNV infection. The brain-infiltrating T lymphocytes dominantly used TCR genes, VA1-1, VA2-1, VB5-2, and VB8-2, and exhibited a highly oligoclonal TCR repertoire. Interestingly, the brain-infiltrating T lymphocytes had different patterns of TCR repertoire usages among WNV-, Japanese encephalitis virus-, and tick-borne encephalitis virus-infected mice. Moreover, CD8+ T cells isolated from the brains of WNV-infected mice produced IFN-γ and TNF-α after in vitro stimulation with peritoneal cells infected with WNV, but not with Japanese encephalitis virus. The results suggest that the infiltrating CD8+ T cells were WNV-specific, but not cross-reactive among flaviviruses. T cells from the WNV-infected brains exhibited identical or similar CDR3 sequences in TCRα among tested mice, but somewhat diverse sequences in TCRβ. The results indicate that WNV-specific CD3+CD8+ T cells expanding in the infected brains are highly oligoclonal, and they suggest that TCR α-chains play a dominant and critical role in Ag specificity of WNV-specific T cells.

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The Memory T Cell Response to West Nile Virus in Symptomatic Humans following Natural Infection Is Not Influenced by Age and Is Dominated by a Restricted Set of CD8+ T Cell Epitopes

Cited by 27 publications

References 38 publications

Low Thymic Activity and Dendritic Cell Numbers Are Associated with the Immune Response to Primary Viral Infection in Elderly Humans

Low Thymic Activity and Dendritic Cell Numbers Are Associated with the Immune Response to Primary Viral Infection in Elderly Humans

West Nile Virus T-Cell Ligand Sequences Shared with Other Flaviviruses: a Multitude of Variant Sequences as Potential Altered Peptide Ligands

High Clonality of Virus-Specific T Lymphocytes Defined by TCR Usage in the Brains of Mice Infected with West Nile Virus

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