Fine-Tuning of Optimal TCR Signaling in Tumor-Redirected CD8 T Cells by Distinct TCR Affinity-Mediated Mechanisms
Redirecting CD8 T cell immunity with self/tumor-specific affinity-matured T cell receptors (TCRs) is a promising approach for clinical adoptive T cell therapy, with the aim to improve treatment efficacy. Despite numerous functional-based studies, little is known about the characteristics of TCR sign...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2017-11-01
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| Series: | Frontiers in Immunology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fimmu.2017.01564/full |
| _version_ | 1819266002742935552 |
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| author | Danilo Presotto Efe Erdes Minh Ngoc Duong Mathilde Allard Pierre-Olivier Regamey Manfredo Quadroni Marie-Agnès Doucey Nathalie Rufer Michael Hebeisen |
| author_facet | Danilo Presotto Efe Erdes Minh Ngoc Duong Mathilde Allard Pierre-Olivier Regamey Manfredo Quadroni Marie-Agnès Doucey Nathalie Rufer Michael Hebeisen |
| author_sort | Danilo Presotto |
| collection | DOAJ |
| description | Redirecting CD8 T cell immunity with self/tumor-specific affinity-matured T cell receptors (TCRs) is a promising approach for clinical adoptive T cell therapy, with the aim to improve treatment efficacy. Despite numerous functional-based studies, little is known about the characteristics of TCR signaling (i.e., intensity, duration, and amplification) and the regulatory mechanisms underlying optimal therapeutic T cell responses. Using a panel of human SUP-T1 and primary CD8 T cells engineered with incremental affinity TCRs against the cancer-testis antigen NY-ESO-1, we found that upon activation, T cells with optimal-affinity TCRs generated intense and sustained proximal (CD3ζ, LCK) signals associated with distal (ERK1/2) amplification-gain and increased function. In contrast, in T cells with very high affinity TCRs, signal initiation was rapid and strong yet only transient, resulting in poor MAPK activation and low proliferation potential even at high antigen stimulation dose. Under resting conditions, the levels of surface TCR/CD3ε, CD8β, and CD28 expression and of CD3ζ phosphorylation were significantly reduced in those hyporesponsive cells, suggesting the presence of TCR affinity-related activation thresholds. We also show that SHP phosphatases were involved along the TCR affinity gradient, but displayed spatially distinct regulatory roles. While PTPN6/SHP-1 phosphatase activity controlled TCR signaling initiation and subsequent amplification by counteracting CD3ζ and ERK1/2 phosphorylation, PTPN11/SHP-2 augmented MAPK activation without affecting proximal TCR signaling. Together, our findings indicate that optimal TCR signaling can be finely tuned by TCR affinity-dependent SHP-1 and SHP-2 activity, and this may readily be determined at the TCR/CD3 complex level. We propose that these TCR affinity-associated regulations represent potential protective mechanisms preventing high affinity TCR-mediated autoimmune diseases. |
| first_indexed | 2024-12-23T20:54:21Z |
| format | Article |
| id | doaj.art-d377c778206f44c5a4950ea4bb835b63 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-23T20:54:21Z |
| publishDate | 2017-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-d377c778206f44c5a4950ea4bb835b632022-12-21T17:31:35ZengFrontiers Media S.A.Frontiers in Immunology1664-32242017-11-01810.3389/fimmu.2017.01564288110Fine-Tuning of Optimal TCR Signaling in Tumor-Redirected CD8 T Cells by Distinct TCR Affinity-Mediated MechanismsDanilo Presotto0Efe Erdes1Minh Ngoc Duong2Mathilde Allard3Pierre-Olivier Regamey4Manfredo Quadroni5Marie-Agnès Doucey6Nathalie Rufer7Michael Hebeisen8Department of Oncology, Lausanne University Hospital Center, University of Lausanne, Lausanne, SwitzerlandDepartment of Oncology, Lausanne University Hospital Center, University of Lausanne, Lausanne, SwitzerlandDepartment of Oncology, Lausanne University Hospital Center, University of Lausanne, Lausanne, SwitzerlandDepartment of Oncology, Lausanne University Hospital Center, University of Lausanne, Lausanne, SwitzerlandProtein Analysis Facility, Center for Integrative Genomics, University of Lausanne, Lausanne, SwitzerlandProtein Analysis Facility, Center for Integrative Genomics, University of Lausanne, Lausanne, SwitzerlandLudwig Institute for Cancer Research, University of Lausanne, Lausanne, SwitzerlandDepartment of Oncology, Lausanne University Hospital Center, University of Lausanne, Lausanne, SwitzerlandDepartment of Oncology, Lausanne University Hospital Center, University of Lausanne, Lausanne, SwitzerlandRedirecting CD8 T cell immunity with self/tumor-specific affinity-matured T cell receptors (TCRs) is a promising approach for clinical adoptive T cell therapy, with the aim to improve treatment efficacy. Despite numerous functional-based studies, little is known about the characteristics of TCR signaling (i.e., intensity, duration, and amplification) and the regulatory mechanisms underlying optimal therapeutic T cell responses. Using a panel of human SUP-T1 and primary CD8 T cells engineered with incremental affinity TCRs against the cancer-testis antigen NY-ESO-1, we found that upon activation, T cells with optimal-affinity TCRs generated intense and sustained proximal (CD3ζ, LCK) signals associated with distal (ERK1/2) amplification-gain and increased function. In contrast, in T cells with very high affinity TCRs, signal initiation was rapid and strong yet only transient, resulting in poor MAPK activation and low proliferation potential even at high antigen stimulation dose. Under resting conditions, the levels of surface TCR/CD3ε, CD8β, and CD28 expression and of CD3ζ phosphorylation were significantly reduced in those hyporesponsive cells, suggesting the presence of TCR affinity-related activation thresholds. We also show that SHP phosphatases were involved along the TCR affinity gradient, but displayed spatially distinct regulatory roles. While PTPN6/SHP-1 phosphatase activity controlled TCR signaling initiation and subsequent amplification by counteracting CD3ζ and ERK1/2 phosphorylation, PTPN11/SHP-2 augmented MAPK activation without affecting proximal TCR signaling. Together, our findings indicate that optimal TCR signaling can be finely tuned by TCR affinity-dependent SHP-1 and SHP-2 activity, and this may readily be determined at the TCR/CD3 complex level. We propose that these TCR affinity-associated regulations represent potential protective mechanisms preventing high affinity TCR-mediated autoimmune diseases.http://journal.frontiersin.org/article/10.3389/fimmu.2017.01564/fullcancer immunotherapyNY-ESO-1 antigenT cell receptor engineeringT cell receptor-peptide-major histocompatibility complex affinityhyporesponsivenessCD3ζ |
| spellingShingle | Danilo Presotto Efe Erdes Minh Ngoc Duong Mathilde Allard Pierre-Olivier Regamey Manfredo Quadroni Marie-Agnès Doucey Nathalie Rufer Michael Hebeisen Fine-Tuning of Optimal TCR Signaling in Tumor-Redirected CD8 T Cells by Distinct TCR Affinity-Mediated Mechanisms Frontiers in Immunology cancer immunotherapy NY-ESO-1 antigen T cell receptor engineering T cell receptor-peptide-major histocompatibility complex affinity hyporesponsiveness CD3ζ |
| title | Fine-Tuning of Optimal TCR Signaling in Tumor-Redirected CD8 T Cells by Distinct TCR Affinity-Mediated Mechanisms |
| title_full | Fine-Tuning of Optimal TCR Signaling in Tumor-Redirected CD8 T Cells by Distinct TCR Affinity-Mediated Mechanisms |
| title_fullStr | Fine-Tuning of Optimal TCR Signaling in Tumor-Redirected CD8 T Cells by Distinct TCR Affinity-Mediated Mechanisms |
| title_full_unstemmed | Fine-Tuning of Optimal TCR Signaling in Tumor-Redirected CD8 T Cells by Distinct TCR Affinity-Mediated Mechanisms |
| title_short | Fine-Tuning of Optimal TCR Signaling in Tumor-Redirected CD8 T Cells by Distinct TCR Affinity-Mediated Mechanisms |
| title_sort | fine tuning of optimal tcr signaling in tumor redirected cd8 t cells by distinct tcr affinity mediated mechanisms |
| topic | cancer immunotherapy NY-ESO-1 antigen T cell receptor engineering T cell receptor-peptide-major histocompatibility complex affinity hyporesponsiveness CD3ζ |
| url | http://journal.frontiersin.org/article/10.3389/fimmu.2017.01564/full |
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