A structure-based approach to designing synthetic CD8α peptides that can inhibit cytotoxic T-lymphocyte responses

Choksi, Swati; Jameson, Bradford A.; Korngold, Robert

doi:10.1038/nm0398-309

Cited by 24 publications

(11 citation statements)

References 34 publications

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“…Membrane-bound CD8aa negatively regulates coreceptor-dependent or coreceptor-independent TCR activation regardless of a productive interaction between its extracellular domain and the antigen-presenting MHC class I molecules (Cawthon et al, 2001). This is in sharp contrast to the potent capacity of soluble CD8aa (sCD8aa) molecules or CD8a-derived peptides to block the interaction between MHC and the CD8ab coreceptor (Choksi et al, 1998;Kern et al, 1999;Sewell et al, 1999). The interference by sCD8aa results in the inhibition of CD3z tyrosine phosphorylation and indicates that the blocking by sCD8aa targets the earliest stage of activation consistent with inhibition of p56 lck activation.…”

Section: Cd8aa Corepressor Functionmentioning

confidence: 93%

Doubting the TCR Coreceptor Function of CD8αα

2008

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"The beginning of wisdom is found in doubting; by doubting we come to question, and by seeking we may come upon the truth." -Pierre Abélard. CD8 is a glycoprotein expressed on hematopoietic cells. Two isoforms of CD8, CD8alphabeta and CD8alphaalpha, have been identified that are distinct in their expression and function. Whereas CD8alphabeta serves as a T cell receptor (TCR) coreceptor to enhance the functional avidity and is constitutively expressed on MHC class I-restricted T cells, CD8alphaalpha marks T cells that are distinct from the conventional thymus-selected and MHC-restricted CD4(+) or CD8alphabeta(+) T cells. Inconsistent with a coreceptor function, CD8alphaalpha decreases antigen sensitivity of the TCR, and it can be transiently or permanently expressed on T cells, regardless of the MHC restriction of the TCR or the presence of conventional coreceptors. Together, these observations indicate that CD8alphaalpha on T cells marks a differentiation stage and that it likely functions as a TCR corepressor to negatively regulate T cell activation.

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Section: Cd8aa Corepressor Functionmentioning

confidence: 93%

Doubting the TCR Coreceptor Function of CD8αα

2008

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“…It has also been suggested that interference with a small number of the multimolecular complexes might alter the quality of the T cell response from an agonist to partial agonist (38,39). Similar mechanisms may explain how a soluble CD8 peptide corresponding to amino acids 54 -59 of CD8 extends the survival of allogeneic skin grafts in vivo (40).…”

Section: Discussionmentioning

confidence: 99%

Soluble CD8 Attenuates Cytotoxic T Cell Responses Against Replication-Defective Adenovirus Affording Transprotection of Transgenes In Vivo

Peng

Falck-Pedersen

Elkon³

2000

The Journal of Immunology

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The T cell coreceptor, CD8, enhances T cell-APC interactions. Because soluble CD8α homodimers can antagonize CD8 T cell activation in vitro, we asked whether secretion of soluble CD8 would effect cytotoxic T cell responses in vivo. Production of soluble CD8 by a replication-defective adenovirus vector allowed persistent virus expression for up to 5 mo in C57BL/6 mice and protected a second foreign transgene from rapid deletion. Soluble CD8 selectively inhibited CD8 T cell proliferation and IFN-γ production and could also attenuate peptide-specific CD8 T cell responses in vivo. These finding suggest that gene vector delivery of soluble CD8 may have therapeutic applications.

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“…The crystal structures of unbound homodimeric CD8 extracellular domain (ECD) and the CD8 /MHC class I complexes indicate that the CD8αα homodimer interacts through all three CDRs with the α3 domain of MHC Class I molecule [47,48]. Using the structural model of murine CD8α as the template in computer simulations, Choksi et al suggested that the CDR-2 like region of CD8 exhibited a folding pattern that is partially independent of the rest of the molecule providing an ideal target for drug design [49]. Screening of multiple peptides from the CD8-CDR-2 loop region identified an octa-peptide (C 51 SSHNKP 57 C) that significantly inhibited cytolytic T cell responses and prolonged skin allograft survival [49].…”

Section: B Cd8 Inhibitorsmentioning

confidence: 99%

Immunomodulatory Peptides from IgSF Proteins: A Review

Srinivasan

Roeske

2005

CPPS

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The immunoglobulin (Ig) domain is a highly conserved domain predominantly observed in cell surface proteins due to its ability to resist proteolysis. By mutation and selection the Ig domain has evolved to serve diverse biological functions including growth and development, signaling, adhesion and protein-carbohydrate interactions. Collectively, proteins with Ig-like domain constitute the immunoglobulin superfamily (IgSF). The IgSF proteins make up over 2% of human genes constituting the largest gene family in the human genome. Analogous to the complementarity determining regions (CDR)s that form the antigen combining sites of the antibody, the high specificity of the IgSF receptor-ligand interaction is attributed to the sequence and structure of the CDR-like regions unique to each IgSF protein. Hence, CDR-like regions provide ideal templates for the design of mimetics that can potentially perturb specific IgSF receptor/ligand interactions. The determinants of binding are localized near the CDR-like regions, conformation is determined locally and is unique for each loop. In structure based drug design one of the approaches to identify lead agents is to map the receptor/ligand binding epitope onto a small peptide. Data from theoretical, structural and functional studies have been adopted in the design of novel peptide antagonists of the IgSF protein-protein interactions. Many peptide antagonists have shown significant therapeutic potential in multiple animal models. The design of the IgSF peptide analogs, rationale as therapeutic targets, functional efficacy and the clinical benefits are reviewed here.

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A structure-based approach to designing synthetic CD8α peptides that can inhibit cytotoxic T-lymphocyte responses

Cited by 24 publications

References 34 publications

Doubting the TCR Coreceptor Function of CD8αα

Doubting the TCR Coreceptor Function of CD8αα

Soluble CD8 Attenuates Cytotoxic T Cell Responses Against Replication-Defective Adenovirus Affording Transprotection of Transgenes In Vivo

Immunomodulatory Peptides from IgSF Proteins: A Review

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