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  • Identification of Highly Cross-Reactive Mimotopes for a Public T Cell Response in Murine Melanoma FRONTIERS IN IMMUNOLOGY Grace, B. E., Backlund, C. M., Morgan, D. M., Kang, B. H., Singh, N. K., Huisman, B. D., Rappazzo, C., Moynihan, K. D., Maiorino, L., Dobson, C. S., Kyung, T., Gordon, K. S., Holec, P., Mbah, O., Garafola, D., Wu, S., Love, J., Wittrup, K., Irvine, D. J., Birnbaum, M. E. 2022; 13: 886683


    While immune checkpoint blockade results in durable responses for some patients, many others have not experienced such benefits. These treatments rely upon reinvigorating specific T cell-antigen interactions. However, it is often unknown what antigens are being recognized by T cells or how to potently induce antigen-specific responses in a broadly applicable manner. Here, we characterized the CD8+ T cell response to a murine model of melanoma following combination immunotherapy to determine the basis of tumor recognition. Sequencing of tumor-infiltrating T cells revealed a repertoire of highly homologous TCR sequences that were particularly expanded in treated mice and which recognized an antigen from an endogenous retrovirus. While vaccination against this peptide failed to raise a protective T cell response in vivo, engineered antigen mimotopes induced a significant expansion of CD8+ T cells cross-reactive to the original antigen. Vaccination with mimotopes resulted in killing of antigen-loaded cells in vivo yet showed modest survival benefit in a prophylactic vaccine paradigm. Together, this work demonstrates the identification of a dominant tumor-associated antigen and generation of mimotopes which can induce robust functional T cell responses that are cross-reactive to the endogenous antigen across multiple individuals.

    View details for DOI 10.3389/fimmu.2022.886683

    View details for Web of Science ID 000821851400001

    View details for PubMedID 35812387

    View details for PubMedCentralID PMC9260506

  • HLA class-I-peptide stability mediates CD8(+) T cell immunodominance hierarchies and facilitates HLA-associated immune control of HIV CELL REPORTS Kaseke, C., Park, R. J., Singh, N. K., Koundakjian, D., Bashirova, A., Beltran, W., Mbah, O., Ma, J., Senjobe, F., Urbach, J. M., Nathan, A., Rossin, E. J., Tano-Menka, R., Khatri, A., Piechocka-Trocha, A., Waring, M. T., Birnbaum, M. E., Baker, B. M., Carrington, M., Walker, B. D., Gaiha, G. D. 2021; 36 (2): 109378


    Defining factors that govern CD8+ T cell immunodominance is critical for the rational design of vaccines for viral pathogens. Here, we assess the contribution of human leukocyte antigen (HLA) class-I-peptide stability for 186 optimal HIV epitopes across 18 HLA alleles using transporter associated with antigen processing (TAP)-deficient mono-allelic HLA-expressing cell lines. We find that immunodominant HIV epitopes increase surface stabilization of HLA class-I molecules in comparison to subdominant epitopes. HLA class-I-peptide stability is also strongly correlated with overall immunodominance hierarchies, particularly for epitopes from high-abundance proteins (e.g., Gag). Moreover, HLA alleles associated with HIV protection are preferentially stabilized by epitopes derived from topologically important viral regions at a greater frequency than neutral and risk alleles. These findings indicate that relative stabilization of HLA class-I is a key factor for CD8+ T cell epitope immunodominance hierarchies, with implications for HIV control and the design of T-cell-based vaccines.

    View details for DOI 10.1016/j.celrep.2021.109378

    View details for Web of Science ID 000672741900034

    View details for PubMedID 34260940

    View details for PubMedCentralID PMC8293625