Modification of the carboxy-terminal flanking region of a universal influenza epitope alters CD4+ T-cell repertoire selection

Cole, David K.; Gallagher, Kathleen; Lemercier, Brigitte; Holland, Christopher; Junaid, Syed; Hindley, James P.; Wynn, Katherine K.; Gostick, Emma; Sewell, Andrew K.; Gallimore, Awen; Ladell, Kristin; Price, David A.; Gougeon, Marie‐Lise; Godkin, Andrew

doi:10.1038/ncomms1665

Cited by 32 publications

(47 citation statements)

References 45 publications

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“…These data show that a range of different modifications to PFRs could modulate specific CD4 + T cell responses including amino acids with biochemically distinct side chains (52, 53). The identification of these PFR amino acid enrichment patterns suggests that they play a role during CD4 + T cell activation and can modulate antigen recognition.…”

Section: Modulating Cd4+ T Cell Responses Via Altered Peptide Flankinmentioning

confidence: 81%

“…The identification of these PFR amino acid enrichment patterns suggests that they play a role during CD4 + T cell activation and can modulate antigen recognition. Further studies using antigen specific CD4 + T cell clones demonstrated that PFR modifications could enhance CD4 + T cell activation (53). Although a wide range of different amino acid substitutions in PFRs could generate stronger CD4 + T cell responses, we observed that basic residues at the peptide C-terminus, or acidic residues in the N-terminus, were most commonly enriched and generated enhanced CD4 + T cell responses across different MHC-II alleles and different peptides.…”

Section: Modulating Cd4+ T Cell Responses Via Altered Peptide Flankinmentioning

confidence: 99%

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Re-Directing CD4+ T Cell Responses with the Flanking Residues of MHC Class II-Bound Peptides: The Core is Not Enough

Holland¹,

Cole²,

Godkin³

2013

Front. Immunol.

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Recombinant αβ T cell receptors, expressed on T cell membranes, recognize short peptides presented at the cell surface in complex with MHC molecules. There are two main subsets of αβ T cells: CD8+ T cells that recognize mainly cytosol-derived peptides in the context of MHC class I (pMHC-I), and CD4+ T cells that recognize peptides usually derived from exogenous proteins presented by MHC class II (pMHC-II). Unlike the more uniform peptide lengths (usually 8–13mers) bound in the MHC-I closed groove, MHC-II presented peptides are of a highly variable length. The bound peptides consist of a core bound 9mer (reflecting the binding motif for the particular MHC-II type) but with variable peptide flanking residues (PFRs) that can extend from both the N- and C-terminus of the MHC-II binding groove. Although pMHC-I and pMHC-II play a virtually identical role during T cell responses (T cell antigen presentation) and are very similar in overall conformation, there exist a number of subtle but important differences that may govern the functional dichotomy observed between CD8+ and CD4+ T cells. Here, we provide an overview of the impact of structural differences between pMHC-I and pMHC-II and the molecular interactions with the T cell receptor including the functional importance of MHC-II PFRs. We consider how factors such as anatomical location, inflammatory milieu, and particular types of antigen presenting cell might, in theory, contribute to the quantitative (i.e., pMHC ligand frequency) as well as qualitative (i.e., variable PFR) nature of peptide epitopes, and hence offer a means of control and influence of a CD4+ T cell response. Lastly, we review our recent findings showing how modifications to MHC-II PFRs can modify CD4+ T cell antigen recognition. These findings may have novel applications for the development of CD4+ T cell peptide vaccines and diagnostics.

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Section: Modulating Cd4+ T Cell Responses Via Altered Peptide Flankinmentioning

confidence: 81%

Section: Modulating Cd4+ T Cell Responses Via Altered Peptide Flankinmentioning

confidence: 99%

Re-Directing CD4+ T Cell Responses with the Flanking Residues of MHC Class II-Bound Peptides: The Core is Not Enough

Holland¹,

Cole²,

Godkin³

2013

Front. Immunol.

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“…In humans, HLA variation is expected to influence the identity of immunodominant and immunoprevalent antigens in specific individuals. Model systems have identified additional factors controlling epitope choice for CD4 T cells, including naïve T-cell repertoire (5), antigen abundance (6), antigen folding (7), protease processing and epitopeflanking regions (8), and antigenic competition (9).…”

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confidence: 99%

CD4 T-Cell Memory Responses to Viral Infections of Humans Show Pronounced Immunodominance Independent of Duration or Viral Persistence

Jing

Schiffer

Chong

et al. 2013

J Virol

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Little is known concerning immunodominance within the CD4 T-cell response to viral infections and its persistence into longterm memory. We tested CD4 T-cell reactivity against each viral protein in persons immunized with vaccinia virus (VV), Immunodominance refers to the proportion of T cells specific for a defined epitope in relation to the entire set of T cells reacting to a complex antigen (1). For infectious pathogens encoding many polypeptides, the immunodominance of an open reading frame (ORF) is the proportion of the total pathogen-specific response accounted for by T cells reacting with this ORF. Immunoprevalence is a related concept, referring to the proportion of a population responding to an immunogen (2). The CD8 T-cell response to complex microbes can show remarkably strong immunodominance in humans and inbred animals.As antigen processing differs between T-cell subsets, it is not clear that immunodominance also applies to CD4 T-cell responses. For VV, memory CD4 T-cell responses in inbred mice are quite polyclonal and do not exhibit dominance. The top 14 epitopes account for only 20% of the total VV-specific CD4 T-cell response (3). Data for the human CD4 T-cell response to cytomegalovirus, in contrast, were somewhat consistent with immunodominance. Subjects recognized a median of 12 ORFs per person (of 213 ORFs studied), with the top 6 ORFs accounting for about 40% of the overall response (4). In humans, HLA variation is expected to influence the identity of immunodominant and immunoprevalent antigens in specific individuals. Model systems have identified additional factors controlling epitope choice for CD4 T cells, including naïve T-cell repertoire (5), antigen abundance (6), antigen folding (7), protease processing and epitopeflanking regions (8), and antigenic competition (9).Vaccinia virus is an orthopoxvirus that causes an infection that resolves completely in several weeks in immunocompetent hosts. CD4 T-cell memory persists for decades despite the absence of antigen reexposure, but little is known about the detailed architecture of long-term memory. The monotonic decline of specific antibody levels supports lack of intermittent boosting (10). VV has over 200 ORFs, so each human has a myriad of potential CD4 reactive T-cell specificities. Herpes simplex virus 1 (HSV-1) also has a complex proteome, but in contrast to self-limited VV infections, HSV-1 infections are chronic with intermittent reactivations. Following initial epithelial replication, the virus establishes persistence in the innervating sensory ganglia. Intermittent reactivation of latent HSV-1 in essentially all HSV-1-infected persons (11) results in periodic viral antigen exposure to HSV-1-specific memory T cells (12).To determine the breadth and persistence of CD4 T-cell immunodominance in acute and chronic human viral infections, we compared patterns of CD4 T-cell immunodominance between recent and remote VV recipients. The immune responses of persons chronically infected with HSV-1 were also investigated as an example of a c...

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“…Nonetheless, the epitope-specific CD4 TCC 7 and 53 did not recognize the nonaHHV orthologous peptides at low concentrations. All nonreactive peptides diverged from the aHHV conserved epitope at HLA-II anchor residues P4, P6, and P9 (43,57). Possibly, the peptides are unable to form stable peptide:HLA-DR complexes or do not functionally engage with the TCR of both TCC.…”

Section: Discussionmentioning

confidence: 99%

“…Immunogenicity of pathogen-derived proteins is determined by various factors including the host T cell repertoire, Ag abundance, size and structure, antigenic competition, and Ag processing (57)(58)(59). VZV IE62 and HSV ICP4 are abundantly expressed viral proteins that are transported from the nucleus to the cytoplasm for incorporation in the tegument of the virion during lytic infection (27,(60)(61)(62).…”

Section: Discussionmentioning

confidence: 99%

Functional Characterization of Ocular-Derived Human Alphaherpesvirus Cross-Reactive CD4 T Cells

Ouwendijk¹,

Geluk

Smits³

et al. 2014

The Journal of Immunology

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Intraocular varicella-zoster virus (VZV) and HSV type 1 (HSV-1) infections cause sight-threatening uveitis. The disease is characterized by an intraocular inflammatory response involving herpesvirus-specific T cells. T cell reactivity to the noncausative human alphaherpesvirus (αHHV) is commonly detected in the affected eyes of herpetic uveitis patients, suggesting the role of cross-reactive T cells in the disease. This study aimed to identify and functionally characterize intraocular human alphaherpesvirus cross-reactive T cells. VZV protein immediate early 62 (IE62), which shares extensive homology with HSV ICP4, is a previously identified T cell target in VZV uveitis. Two VZV-specific CD4 T cell clones (TCC), recovered from the eye of a VZV uveitis patient, recognized the same IE62918–927 peptide using different TCR and HLA-DR alleles. The IE62918–927 peptide bound with high affinity to multiple HLA-DR alleles and was recognized by blood-derived T cells of 5 of 17 HSV-1/VZV-seropositive healthy adults but not in cord blood donors (n = 5). Despite complete conservation of the IE62 epitope in the orthologous protein ICP4 of HSV-1 and HSV-2, the TCC recognized VZV and HSV-1– but not HSV-2–infected B cells. This was not attributed to proximal epitope-flanking amino acid polymorphisms in HSV-2 ICP4. Notably, VZV/HSV-1 cross-reactive CD4 T cells controlled VZV but not HSV-1 infection of human primary retinal pigment epithelium (RPE) cells. In conclusion, we report on the first VZV/HSV-1 cross-reactive CD4 T cell epitope, which is HLA-DR promiscuous and immunoprevalent in coinfected individuals. Moreover, ocular-derived peptide-specific CD4 TCC controlled VZV but not HSV-1 infection of RPE cells, suggesting that HSV-1 actively inhibits CD4 T cell activation by infected human RPE cells.

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Modification of the carboxy-terminal flanking region of a universal influenza epitope alters CD4+ T-cell repertoire selection

Cited by 32 publications

References 45 publications

Re-Directing CD4+ T Cell Responses with the Flanking Residues of MHC Class II-Bound Peptides: The Core is Not Enough

Re-Directing CD4+ T Cell Responses with the Flanking Residues of MHC Class II-Bound Peptides: The Core is Not Enough

CD4 T-Cell Memory Responses to Viral Infections of Humans Show Pronounced Immunodominance Independent of Duration or Viral Persistence

Functional Characterization of Ocular-Derived Human Alphaherpesvirus Cross-Reactive CD4 T Cells

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