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Backbone Modifications of HLA-A2-Restricted Antigens Induce Diverse Binding and T Cell Activation Outcomes.

ABSTRACT: CD8⁺ T cells express T cell receptors (TCRs) that recognize short peptide antigens in the context of major histocompatibility class I (MHC I) molecules. This recognition process produces an array of cytokine-mediated signals that help to govern immunological responses. Design of biostable MHC I peptide vaccines containing unnatural subunits is desirable, and synthetic antigens in which a native α-amino acid residue is replaced by a homologous β-amino acid residue (native side chain but extended backbone) might be useful in this regard. We have evaluated the impact of α-to-β backbone modification at a single site on T cell-mediated recognition of six clinically important viral and tumor-associated antigens bound to an MHC I. Effects of this modification on MHC I affinity and T cell activation were measured. Many of these modifications diminish or prevent T cell response. However, a number of α/β-peptide antigens were found to mimic the activity of natural antigens or to enhance maximal T cell response, as measured by interferon-γ release. Results from this broad exploratory study advance our understanding of immunological responses to antigens bearing unnatural modifications and suggest that α/β-peptides could be a source of potent and proteolytically stable variants of native antigens.

SUBMITTER: Gibadullin R

PROVIDER: S-EPMC8111684 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Backbone Modifications of HLA-A2-Restricted Antigens Induce Diverse Binding and T Cell Activation Outcomes.

Gibadullin Ruslan R Randall Caleb J CJ Sidney John J Sette Alessandro A Gellman Samuel H SH

Journal of the American Chemical Society 20210421 17

CD8<sup>+</sup> T cells express T cell receptors (TCRs) that recognize short peptide antigens in the context of major histocompatibility class I (MHC I) molecules. This recognition process produces an array of cytokine-mediated signals that help to govern immunological responses. Design of biostable MHC I peptide vaccines containing unnatural subunits is desirable, and synthetic antigens in which a native α-amino acid residue is replaced by a homologous β-amino acid residue (native side chain bu ...[more]

PMID: 33881854

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Project description:NY-ESO-1 is a tumor-specific, highly immunogenic, human germ cell antigen of the MAGE-1 family that is a promising vaccine and cell therapy candidate in clinical trial development. The mouse genome does not encode an NY-ESO-1 homolog thereby not subjecting transgenic T-cells to thymic tolerance mechanisms that might impair in-vivo studies. We hypothesized that an NY-ESO-1 T cell receptor (TCR) transgenic mouse would provide the unique opportunity to study avidity of TCR response against NY-ESO-1 for tumor vaccine and cellular therapy development against this clinically relevant and physiological human antigen. To study in vitro and in vivo the requirements for shaping an effective T cell response against the clinically relevant NY-ESO-1, we generated a C57BL/6 HLA-A*0201 background TCR transgenic mouse encoding the 1G4 TCR specific for the human HLA-A2 restricted, NY-ESO-1157-165 SLLMWITQC (9C), initially identified in an NY-ESO-1 positive melanoma patient. The HLA-A*0201 restricted TCR was positively selected on both CD4+ and CD8+ cells. Mouse 1G4 T cells were not activated by endogenous autoimmune targets or a large library of non-cognate viral antigens. In contrast, their activation by HLA-A2 NY-ESO-1157-165 complexes was evident by proliferation, CD69 upregulation, interferon-γ production, and interleukin-2 production, and could be tuned using a twofold higher affinity altered peptide ligand, NY-ESO-1157-165V. NY-ESO-1157-165V recombinant vaccination of syngeneic mice adoptively transferred with m1G4 CD8+ T cells controlled tumor growth in vivo. 1G4 transgenic mice suppressed growth of syngeneic methylcholanthrene (MCA) induced HHD tumor cells expressing the full-length human NY-ESO-1 protein but not MCA HHD tumor cells lacking NY-ESO-1. The 1G4 TCR mouse model for the physiological human TCR against the clinically relevant antigen, NY-ESO-1, is a valuable tool with the potential to accelerate clinical development of NY-ESO-1-targeted T-cell and vaccine therapies.

Dataset Information

Backbone Modifications of HLA-A2-Restricted Antigens Induce Diverse Binding and T Cell Activation Outcomes.

Publications

Backbone Modifications of HLA-A2-Restricted Antigens Induce Diverse Binding and T Cell Activation Outcomes.

Similar Datasets

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