Altered Binding of Tumor Antigenic Peptides to MHC Class I Affects CD8+ T Cell–Effector Responses
T-cell priming occurs when a na€ve T cell recognizes cognate peptide–MHC complexes on an activated antigen-presenting cell. The circumstances of this initial priming have ramifications on the fate of the newly primed T cell. Newly primed CD8þ T cells can embark onto different trajectories, with some...
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| Format: | Article |
| Language: | English |
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American Association for Cancer Research (AACR)
2020
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| Online Access: | https://hdl.handle.net/1721.1/124836 |
| _version_ | 1826190176901136384 |
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| author | Devlin, Christine A. Birnbaum, Michael E. |
| author2 | Koch Institute for Integrative Cancer Research at MIT |
| author_facet | Koch Institute for Integrative Cancer Research at MIT Devlin, Christine A. Birnbaum, Michael E. |
| author_sort | Devlin, Christine A. |
| collection | MIT |
| description | T-cell priming occurs when a na€ve T cell recognizes cognate peptide–MHC complexes on an activated antigen-presenting cell. The circumstances of this initial priming have ramifications on the fate of the newly primed T cell. Newly primed CD8þ T cells can embark onto different trajectories, with some becoming short-lived effector cells and others adopting a tissue resident or memory cell fate. To determine whether T-cell priming influences the quality of the effector T-cell response to tumors, we used transnuclear CD8þ T cells that recognize the melanoma antigen TRP1 using TRP1high or TRP1low TCRs that differ in both affinity and fine specificity. From a series of altered peptide ligands, we identified a point mutation (K8) in a nonanchor residue that, when analyzed crystallographically and biophysically, destabilized the peptide interaction with the MHC binding groove. In vitro, the K8 peptide induced robust proliferation of both TRP1high and TRP1low CD8þ T cells but did not induce expression of PD-1. Cytokine production from K8-stimulated TRP1 cells was minimal, whereas cytotoxicity was increased. Upon transfer into B16 tumor–bearing mice, the reference peptide (TRP1-M9)- and K8-stimulated TRP1 cells were equally effective at controlling tumor growth but accomplished this through different mechanisms. TRP1-M9–stimulated cells produced more IFNg, whereas K8-stimulated cells accumulated to higher numbers and were more cytotoxic. We, therefore, conclude that TCR recognition of weakly binding peptides during priming can skew the effector function of tumor-specific CD8þ T cells. |
| first_indexed | 2024-09-23T08:36:16Z |
| format | Article |
| id | mit-1721.1/124836 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T08:36:16Z |
| publishDate | 2020 |
| publisher | American Association for Cancer Research (AACR) |
| record_format | dspace |
| spelling | mit-1721.1/1248362022-09-23T13:14:14Z Altered Binding of Tumor Antigenic Peptides to MHC Class I Affects CD8+ T Cell–Effector Responses Devlin, Christine A. Birnbaum, Michael E. Koch Institute for Integrative Cancer Research at MIT T-cell priming occurs when a na€ve T cell recognizes cognate peptide–MHC complexes on an activated antigen-presenting cell. The circumstances of this initial priming have ramifications on the fate of the newly primed T cell. Newly primed CD8þ T cells can embark onto different trajectories, with some becoming short-lived effector cells and others adopting a tissue resident or memory cell fate. To determine whether T-cell priming influences the quality of the effector T-cell response to tumors, we used transnuclear CD8þ T cells that recognize the melanoma antigen TRP1 using TRP1high or TRP1low TCRs that differ in both affinity and fine specificity. From a series of altered peptide ligands, we identified a point mutation (K8) in a nonanchor residue that, when analyzed crystallographically and biophysically, destabilized the peptide interaction with the MHC binding groove. In vitro, the K8 peptide induced robust proliferation of both TRP1high and TRP1low CD8þ T cells but did not induce expression of PD-1. Cytokine production from K8-stimulated TRP1 cells was minimal, whereas cytotoxicity was increased. Upon transfer into B16 tumor–bearing mice, the reference peptide (TRP1-M9)- and K8-stimulated TRP1 cells were equally effective at controlling tumor growth but accomplished this through different mechanisms. TRP1-M9–stimulated cells produced more IFNg, whereas K8-stimulated cells accumulated to higher numbers and were more cytotoxic. We, therefore, conclude that TCR recognition of weakly binding peptides during priming can skew the effector function of tumor-specific CD8þ T cells. National Institutes of Health (U.S.) (Grant P30-CA14051) 2020-04-23T16:49:46Z 2020-04-23T16:49:46Z 2018-10-23 2020-03-04T17:31:33Z Article http://purl.org/eprint/type/JournalArticle 2326-6066 2326-6074 https://hdl.handle.net/1721.1/124836 Clancy-Thompson, Eleanor et al. “Altered Binding of Tumor Antigenic Peptides to MHC Class I Affects CD8+ T Cell–Effector Responses.” Cancer immunology research 6 (2018): 1524-1536 © 2018 The Author(s) en 10.1158/2326-6066.cir-18-0348 Cancer immunology research Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association for Cancer Research (AACR) PMC |
| spellingShingle | Devlin, Christine A. Birnbaum, Michael E. Altered Binding of Tumor Antigenic Peptides to MHC Class I Affects CD8+ T Cell–Effector Responses |
| title | Altered Binding of Tumor Antigenic Peptides to MHC Class I Affects CD8+ T Cell–Effector Responses |
| title_full | Altered Binding of Tumor Antigenic Peptides to MHC Class I Affects CD8+ T Cell–Effector Responses |
| title_fullStr | Altered Binding of Tumor Antigenic Peptides to MHC Class I Affects CD8+ T Cell–Effector Responses |
| title_full_unstemmed | Altered Binding of Tumor Antigenic Peptides to MHC Class I Affects CD8+ T Cell–Effector Responses |
| title_short | Altered Binding of Tumor Antigenic Peptides to MHC Class I Affects CD8+ T Cell–Effector Responses |
| title_sort | altered binding of tumor antigenic peptides to mhc class i affects cd8 t cell effector responses |
| url | https://hdl.handle.net/1721.1/124836 |
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