A Peptide That Antagonizes TCR-Mediated Reactions with Both Syngeneic and Allogeneic Agonists: Functional and Structural Aspects

Rudolph, M.G.; Shen, Lucy Q.; Lamontagne, Stephen A.; Luz, J.G.; Delaney, Joseph R.; Ge, Qing; Cho, Bryan K.; Palliser, Deborah; McKinley, Carol A.; Chen, Jianzhu; Wilson, Ian A.; Eisen, Herman N.

doi:10.4049/jimmunol.172.5.2994

Cited by 14 publications

(10 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Of particular interest was that this antagonist peptide could effectively inhibit this alloreactivity. Recently, an APL that antagonizes syngeneic and allogeneic agonists in the mouse 2C system has been described (45). The present report reinforces the proposal that TCR antagonist peptides could find application as specific therapeutics for GVHD and allograft rejection in humans.…”

Section: Hla-b8supporting

confidence: 74%

Antagonism of Antiviral and Allogeneic Activity of a Human Public CTL Clonotype by a Single Altered Peptide Ligand: Implications for Allograft Rejection

Ely

Green

Beddoe

et al. 2005

The Journal of Immunology

View full text Add to dashboard Cite

Alloreactive T lymphocytes are central mediators of graft-versus-host disease and allograft rejection. A public CTL clonotype with specificity for the alloantigens HLA-B*4402 and B*4405 is often expanded to large numbers in healthy HLA-B*0801+ individuals, driven by cross-reactive stimulation with the common, persistent herpesvirus EBV. Since such alloreactive memory CTL expansions have the potential to influence transplantation outcome, altered peptide ligands (APLs) of the target HLA-B*0801-binding EBV peptide, FLRGRAYGL, were screened as specific antagonists for this immunodominant clonotype. One APL, FLRGRFYGL, exerted powerful antagonism of a prototypic T cell clone expressing this immunodominant TCR when costimulated with target cells presenting HLA-B*0801FLRGRAYGL. Significantly, this APL also reduced the lysis of allogeneic target cells expressing HLA-B*4402 by up to 99%. The affinities of the agonist and antagonist complexes for the public TCR, measured using solution and solid-phase assays, were 8 and 138 μM, respectively. Surprisingly, the half-life of the agonist and antagonist complexes was similar, yet the association rate for the antagonist complex was significantly slower. These observations were further supported by structural studies that suggested a large conformational hurdle was required to ligate the immunodominant TCR to the HLA-B*0801 antagonist complex. By defining an antagonist APL against an immunodominant alloreactive TCR, these findings raise the prospect of exploiting such peptides to inhibit clinical alloreactivity, particularly against clonal T cell expansions that react with alloantigens.

show abstract

Section: Hla-b8supporting

confidence: 74%

Antagonism of Antiviral and Allogeneic Activity of a Human Public CTL Clonotype by a Single Altered Peptide Ligand: Implications for Allograft Rejection

Ely

Green

Beddoe

et al. 2005

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…In addition to the wild-type receptor, a series of engineered TCR mutants that bind with various affinities to both ligands have been made and characterized (16, 21, 22). Antagonism has been shown previously for the 2C TCR in CD8-positive T cells by various synthetic peptides presented by the syngeneic MHC H2-K b (23); however, antagonism had not been shown for this TCR without expression of the CD8 co-receptor. To examine the relationships of TCR binding affinity and antagonism in the absence of co-receptor, we determined whether T cell hybridomas that express CD8-independent TCRs (2C or a higher affinity 2C mutant m33 and its derivatives) without CD8, could be antagonized by altered peptide ligands (APLs).…”

Section: Resultsmentioning

confidence: 79%

Opposite Effects of Endogenous Peptide–MHC Class I on T Cell Activity in the Presence and Absence of CD8

Stone

Aggen

Chervin

et al. 2011

The Journal of Immunology

View full text Add to dashboard Cite

Non-stimulatory or endogenous pepMHC presented on the surface of APCs, either alone or alongside agonist pepMHC, play various roles in T cell selection and activation. To examine these properties in more detail, here we explored several model systems of TCR and pepMHC ligands with sufficient affinity to be activated in the absence of CD8. The TCRs had a range of affinities for agonist and non-stimulatory ligands, and were restricted by class I MHC alleles with different properties. We observed CD8-independent antagonism from TCR:pepMHC interactions with very low affinities (e.g. KD = 300μM). In addition, endogenous pep/Ld complexes on APCs antagonized activation of co-receptor (CD8)-negative 2C T cells even by the strong agonist QL9/Ld. In contrast, TCRs m33 and 3D-PYY, restricted by Kb and Db, respectively, did not show signs of antagonism by endogenous pepMHC in the absence of CD8. This did not appear to be an inherent difference in the ability of the TCRs to be antagonized, as altered peptide ligands could antagonize each TCR. In the presence of CD8, endogenous pepMHC ligands acted in some cases as co-agonists. These results show that endogenous pepMHC molecules exhibit complex behavior in T cells, leading to either reduced activity (e.g. in cases of low co-receptor levels) or enhanced activity (e.g. in presence of co-receptor). The behavior may be influenced by the ability of different TCRs to recognize endogenous pepMHC, but also perhaps by the inherent properties of the presenting MHC allele.

show abstract

“…(A) Structures of hβ 2 m (Protein Data Bank [PDB] ID code 2XKS), ΔΝ6 (PDB ID code 2XKU) (Eichner et al., 2011), and mβ 2 m (PDB ID code 1LK2) (Rudolph et al., 2004) (left to right).…”

Section: Figurementioning

confidence: 99%

Visualization of Transient Protein-Protein Interactions that Promote or Inhibit Amyloid Assembly

et al. 2014

View full text Add to dashboard Cite

SummaryIn the early stages of amyloid formation, heterogeneous populations of oligomeric species are generated, the affinity, specificity, and nature of which may promote, inhibit, or define the course of assembly. Despite the importance of the intermolecular interactions that initiate amyloid assembly, our understanding of these events remains poor. Here, using amyloidogenic and nonamyloidogenic variants of β2-microglobulin, we identify the interactions that inhibit or promote fibril formation in atomic detail. The results reveal that different outcomes of assembly result from biomolecular interactions involving similar surfaces. Specifically, inhibition occurs via rigid body docking of monomers in a head-to-head orientation to form kinetically trapped dimers. By contrast, the promotion of fibrillation involves relatively weak protein association in a similar orientation, which results in conformational changes in the initially nonfibrillogenic partner. The results highlight the complexity of interactions early in amyloid assembly and reveal atomic-level information about species barriers in amyloid formation.

show abstract

A Peptide That Antagonizes TCR-Mediated Reactions with Both Syngeneic and Allogeneic Agonists: Functional and Structural Aspects

Cited by 14 publications

References 57 publications

Antagonism of Antiviral and Allogeneic Activity of a Human Public CTL Clonotype by a Single Altered Peptide Ligand: Implications for Allograft Rejection

Antagonism of Antiviral and Allogeneic Activity of a Human Public CTL Clonotype by a Single Altered Peptide Ligand: Implications for Allograft Rejection

Opposite Effects of Endogenous Peptide–MHC Class I on T Cell Activity in the Presence and Absence of CD8

Visualization of Transient Protein-Protein Interactions that Promote or Inhibit Amyloid Assembly

Contact Info

Product

Resources

About