Highly conserved pattern of recognition of influenza A wild-type and variant CD8+ CTL epitopes in HLA-A2+ humans and transgenic HLA-A2+/H2 class I-deficient mice

Hu, Ningjie; D’Souza, Celine; Cheung, Heidi; Lang, Haili; Cheuk, Eve; Chamberlain, John W.

doi:10.1016/j.vaccine.2005.07.032

Cited by 13 publications

(17 citation statements)

References 39 publications

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“…Our study with influenza infection confirm previous findings where high avidity T cells were deleted following, but not before, HIV-1 and EBV infection in individuals co-expressing various HLA-A, -B, and -C alleles [29]. Furthermore, although it is possible that other B27-specific CD8 + T-cell subsets expressing Vβ chains other than those examined may have been deleted and thus contributed to the reduced level of B27/NP383-restricted CTL response in B7/B27 Tg mice, this seems unlikely based on published results [12,13,33]. Flu-specific tetramer staining with HLA Tg chimeras and nonchimeras confirmed that negative selection in the thymus of B7/B27 Tg mice is involved in deleting some B27/NP383-restricted Vβ8.1 + CD8 + naive T cells and this deletion occurs only when B27 is co-expressed with B7.…”

Section: Discussionmentioning

confidence: 98%

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Co‐expression of HLA‐B7 and HLA‐B27 alleles is associated with B7‐restricted immunodominant responses following influenza infection

Akram

Inman

2013

Eur J Immunol

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It is recognized that host response following viral infection is characterized by immunodominance, but deciphering the different factors contributing to immunodominance has proved a challenge due to concurrent expression of multiple MHC class I alleles. To address this, we generated H2-K −/− /D −/− double-knockout transgenic mice expressing either one or two human MHC-I alleles. We hypothesized that co-expression of different allele combinations figures critically in immunodominance and examined this in influenza-infected, double Tg MHC-I mice. In A2/B7 or A2/B27 mice, using ELISpot assays with the A2-restricted matrix I.58-66, the B7-restricted NP418-426 or the B27-restricted NP383-391 influenza A (flu) epitopes, we observed the expected recognition of both peptides for both alleles. In contrast, in flu-infected B7/B27 mice, a significantly reduced level of B27/NP383-restricted CTL response was detected while there was no change in the B7/NP418-restricted CTL response. Flu-specific tetramer studies revealed a partial deletion of Vβ8.1 + NP383/B27-restricted CD8 + T cells, and a diminished Vβ12 + CD8 + T-cell expansion in B7/B27 Tg mice. Using HLA Tg chimeric mice, we confirmed these findings. These findings shed light on the immune consequences of co-dominant expression of MHC-I alleles for host immune response to pathogens.Keywords: HLA-B7 and HLA-B27 r Immunodominance r Influenza A r Thymic selection Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe cellular immune response to a viral infection depends on the ability of CTLs to recognize, via their TCR, viral antigenic peptides in the context of major histocompatibility complex class I molecules (MHC-I) [1]. Following a viral infection, viral peptides are bound by MHC class I molecules and transported to the cell Correspondence: Dr. Robert D. Inman e-mail: robert.inman@uhn.ca surface where they are surveyed for recognition by the repertoire of αβ-TCR expressed by CTLs [2]. In this context, immunodominance refers to the phenomenon whereby a large fraction of the antiviral CTL population is directed against a limited number of MHC class I/peptide complexes (i.e. pMHC-I). The viral peptide that dominates CTL recognition with a particular MHC allele is referred to as the immunodominant (ImD) epitope. As we recently reviewed [3], the mechanisms of immunodominance are not completely understood, but almost every step in antigen processing and presentation may contribute to determine which specific peptide sequences will be available for recognition by CTLs [4].C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2013. 43: 3254-3267 Immunity to infection 3255Immunodominance is very common in host response to viral pathogens. Immunodominant responses have been observed to a range of pathogens including hepatitis B virus [5,6], Epstein Barr virus (EBV) [7,8], and cytomegalovirus (CMV) [9,10]. As analysis of antiviral T-cell responses for humans is complica...

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Section: Discussionmentioning

confidence: 98%

“…M1.58-66) [13,14], B7-restricted flu nucleoprotein (NP) NP418-426 [13] and B27-restricted flu NP383-391 epitopes [12,15]. Thus, these transgenic mice can be instructive for investigating factors leading to immunodominance.…”

Section: Double-knockout (Dko)) Studies Demonstrated That Influenza mentioning

confidence: 99%

Co‐expression of HLA‐B7 and HLA‐B27 alleles is associated with B7‐restricted immunodominant responses following influenza infection

Akram

Inman

2013

Eur J Immunol

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“…The generation of single Tg HLA-B27/DKO and HLA-B7/DKO has been described (8,16). The generation of ERAP-deficient mice has also been described (9).…”

Section: Methodsmentioning

confidence: 99%

HLA-B27, but Not HLA-B7, Immunodominance to Influenza Is ERAP Dependent

Akram

Lin

Gracey

et al. 2014

The Journal of Immunology

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Endoplasmic reticulum–associated aminopeptidase-1 (ERAP1) plays a critical role in the processing of peptides prior to binding to MHC class I molecules. In this article, we show for the first time, to our knowledge, that the HLA-B27 immunodominant influenza nucleoprotein (NP) 383–391 epitope is made as an N-terminally extended 14-mer before it is trimmed by ERAP. In the absence of ERAP, there is a significant reduction in the CTL response to the B27/NP383–391 epitope in influenza A (flu)–infected B27/ERAP−/− mice. With the use of tetramer staining, the number of naive CD8+ T cells expressing TCR Vβ8.1 in B27/ERAP−/− transgenic mice is significantly lower than that seen in B27/ERAP+/+ mice. HLA-B27 surface expression in naive and flu-infected B27/ERAP−/− mice is also lower than the expression seen for the same allele in naive and flu-infected B27/ERAP+/+ mice. In contrast, surface expression of HLA-B7 was unaffected by the absence of ERAP in B7/ERAP−/− transgenic mice. The B7-restricted NP418–426 CTL response in flu-infected B7/ERAP−/− and B7/ERAP+/+ mice was also similar. These results provide, to our knowledge, the first in vivo demonstration of ERAP functionally influencing host immune response in an HLA allele-specific manner. This principle has relevance to diseases such as ankylosing spondylitis, in which HLA-B27 and ERAP jointly contribute to disease predisposition.

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“…WNV T-cell ligand sequences were identified by use of HLA transgenic 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), as follows: H-2 class II deficient, HLA-DR2 (DRB1*1501) (68), HLA-DR3 (DRB1*0301) (29,64), and HLA-DR4 (DRB1*0401)/human CD4 (huCD4) (6,10); and H-2 class I deficient, HLA-A2.1 (A*0201) (HHD monochain) (44), HLA-A24 (A*2402)/huCD8␣ (F. Lemonnier unpublished data), and HLA-B7 (B*0702) (51). HLA-DR2 transgenic mice express chimeric molecules, with ␣1 and ␤1 domains encoded by the HLA-DRA1*0101 and -DRB1*1501 sequences and the other domains encoded by I-E␣ and I-E␤ sequences from the I-E promoters (68).…”

Section: Methodsmentioning

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). Six mice transgenic for prototype HLA proteins, 3 class I and 3 class II, were immunized with 452 peptides covering the entire WNV proteome and peptide-specific T-cell responses were assayed by gamma interferon (IFN-␥) enzyme-linked immunosorbent spot (ELISpot) assay.…”

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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Highly conserved pattern of recognition of influenza A wild-type and variant CD8+ CTL epitopes in HLA-A2+ humans and transgenic HLA-A2+/H2 class I-deficient mice

Cited by 13 publications

References 39 publications

Co‐expression of HLA‐B7 and HLA‐B27 alleles is associated with B7‐restricted immunodominant responses following influenza infection

Co‐expression of HLA‐B7 and HLA‐B27 alleles is associated with B7‐restricted immunodominant responses following influenza infection

HLA-B27, but Not HLA-B7, Immunodominance to Influenza Is ERAP Dependent

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

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