Strong memory CD8+ T cell responses against immunodominant and three new subdominant HLA-B27-restricted influenza A CTL epitopes following secondary infection of HLA-B27 transgenic mice

Cheuk, Eve; Chamberlain, John W.

doi:10.1016/j.cellimm.2005.06.004

Cited by 11 publications

(7 citation statements)

References 48 publications

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“…We chose to investigate a variety of HLA-B27 restricted peptides in our studies to determine if pathogen derived, or autologous peptides, (that have both been previously shown to correlate with AS) may show ERAP1 allele specific differences when processed for HLA-B27 surface expression. (Supplemental Table II) (41, 43, 46–52). Transfection efficiencies were found to be high, with double positive cells averaging ~7.5% of the cells in each experiment (Supplemental Figure 3).…”

Section: Resultsmentioning

confidence: 99%

Endoplasmic reticulum aminopeptidase-1 alleles associated with increased risk of ankylosing spondylitis reduce HLA-B27 mediated presentation of multiple antigens

et al. 2013

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Ankylosing spondylitis (AS) is a chronic systemic arthritic disease that leads to significant disability and loss of quality of life in the ~0.5% of the worldwide human population it affects. There is currently no cure for AS and mechanisms underlying its pathogenesis remain unclear. AS is highly genetic, with over 70% of the genetic risk being associated with the presence of HLA-B27 and endoplasmic reticulum aminopeptidase-1 (ERAP1) alleles. Furthermore, gene-gene interactions between HLA-B27 and ERAP1 AS risk alleles have recently been confirmed. Here, we demonstrate that various ERAP1 alleles can differentially mediate surface expression of antigens presented by HLA-B27 on human cells. Specifically, for all peptides tested, we found that an ERAP1 variant containing high AS risk SNPs reduced the amount of the peptide presented by HLA-B27, relative to low AS risk ERAP1 variants. These results were further validated using peptide catalysis assays in vitro, suggesting that high AS risk alleles have an enhanced catalytic activity that more rapidly destroys many HLA-B27-destined peptides, a result that correlated with decreased HLA-B27 presentation of the same peptides. These findings suggest that one mechanism underlying AS pathogenesis may involve an altered ability for AS patients harboring both HLA-B27 and high AS risk ERAP1 alleles to correctly display a variety of peptides to the adaptive arm of the immune system, potentially exposing such individuals to higher AS risk due to abnormal display of pathogen or self derived peptides by the adaptive immune system.

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Section: Resultsmentioning

confidence: 99%

Endoplasmic reticulum aminopeptidase-1 alleles associated with increased risk of ankylosing spondylitis reduce HLA-B27 mediated presentation of multiple antigens

et al. 2013

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“…While cellular immunity is not sterilizing, it prevents illness and death in animal models ( 3 ). Common and immunodominant epitopes among circulating nonavian strains have been identified, and many of the same models and algorithms can be used to make predictions against the pathogenic strains ( 51 ). Mouse models are now available that have human leukocyte antigen (HLA) alleles, and they appear to recapitulate human epitope use.…”

Section: Cell-mediated Vaccine For Highly Pathogenic Influenza?mentioning

confidence: 99%

Cell-mediated Protection in Influenza Infection

Thomas

Keating

Hulse-Post

et al. 2006

Emerg. Infect. Dis.

423

391

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“…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%

“…Here we have generated three novel double HLA Tg strains, referred hereafter as A2/B7, A2/B27, and B7/B27, respectively. The Tg A2/B7 and -A2/B27 strains have been briefly described previously [11,12,15]. This is the first description of the B7/B27 Tg strain.…”

Section: Characterization Of a Novel Tg Hla-b7/b27/h2 Double-knockoutmentioning

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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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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Strong memory CD8+ T cell responses against immunodominant and three new subdominant HLA-B27-restricted influenza A CTL epitopes following secondary infection of HLA-B27 transgenic mice

Cited by 11 publications

References 48 publications

Endoplasmic reticulum aminopeptidase-1 alleles associated with increased risk of ankylosing spondylitis reduce HLA-B27 mediated presentation of multiple antigens

Endoplasmic reticulum aminopeptidase-1 alleles associated with increased risk of ankylosing spondylitis reduce HLA-B27 mediated presentation of multiple antigens

Cell-mediated Protection in Influenza Infection

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

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