Manipulation of diacylglycerol and ERK-mediated signaling differentially controls CD8+ T cell responses during chronic viral infection
IntroductionActivation of T cell receptor (TCR) signaling is critical for clonal expansion of CD8+ T cells. However, the effects of augmenting TCR signaling during chronic antigen exposure is less understood. Here, we investigated the role of diacylglycerol (DAG)-mediated signaling downstream of the...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-11-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.1032113/full |
| _version_ | 1811179750037651456 |
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| author | Shohei Harabuchi Shohei Harabuchi Omar Khan Hamid Bassiri Taku Yoshida Yohei Okada Masaomi Takizawa Osamu Ikeda Akihiro Katada Taku Kambayashi |
| author_facet | Shohei Harabuchi Shohei Harabuchi Omar Khan Hamid Bassiri Taku Yoshida Yohei Okada Masaomi Takizawa Osamu Ikeda Akihiro Katada Taku Kambayashi |
| author_sort | Shohei Harabuchi |
| collection | DOAJ |
| description | IntroductionActivation of T cell receptor (TCR) signaling is critical for clonal expansion of CD8+ T cells. However, the effects of augmenting TCR signaling during chronic antigen exposure is less understood. Here, we investigated the role of diacylglycerol (DAG)-mediated signaling downstream of the TCR during chronic lymphocytic choriomeningitis virus clone 13 (LCMV CL13) infection by blocking DAG kinase zeta (DGKζ), a negative regulator of DAG.MethodsWe examined the activation, survival, expansion, and phenotype of virus-specific T cell in the acute and chronic phases of LCMV CL13-infected in mice after DGKζ blockade or selective activation of ERK.ResultsUpon LCMV CL13 infection, DGKζ deficiency promoted early short-lived effector cell (SLEC) differentiation of LCMV-specific CD8+ T cells, but this was followed by abrupt cell death. Short-term inhibition of DGKζ with ASP1570, a DGKζ-selective pharmacological inhibitor, augmented CD8+ T cell activation without causing cell death, which reduced virus titers both in the acute and chronic phases of LCMV CL13 infection. Unexpectedly, the selective enhancement of ERK, one key signaling pathway downstream of DAG, lowered viral titers and promoted expansion, survival, and a memory phenotype of LCMV-specific CD8+ T cells in the acute phase with fewer exhausted T cells in the chronic phase. The difference seen between DGKζ deficiency and selective ERK enhancement could be potentially explained by the activation of the AKT/mTOR pathway by DGKζ deficiency, since the mTOR inhibitor rapamycin rescued the abrupt cell death seen in virus-specific DGKζ KO CD8+ T cells.DiscussionThus, while ERK is downstream of DAG signaling, the two pathways lead to distinct outcomes in the context of chronic CD8+ T cell activation, whereby DAG promotes SLEC differentiation and ERK promotes a memory phenotype. |
| first_indexed | 2024-04-11T06:39:48Z |
| format | Article |
| id | doaj.art-e0860c9208fd4250ad3c790230b9590a |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-11T06:39:48Z |
| publishDate | 2022-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-e0860c9208fd4250ad3c790230b9590a2022-12-22T04:39:35ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-11-011310.3389/fimmu.2022.10321131032113Manipulation of diacylglycerol and ERK-mediated signaling differentially controls CD8+ T cell responses during chronic viral infectionShohei Harabuchi0Shohei Harabuchi1Omar Khan2Hamid Bassiri3Taku Yoshida4Yohei Okada5Masaomi Takizawa6Osamu Ikeda7Akihiro Katada8Taku Kambayashi9Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United StatesDepartment of Otolaryngology-Head and Neck surgery, Asahikawa Medical University, Asahikawa, JapanDepartment of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, United StatesDivision of Infectious Diseases, Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United StatesImmuno-Oncology, Astellas Pharma Inc., Tsukuba, JapanImmuno-Oncology, Astellas Pharma Inc., Tsukuba, JapanResearch Program Management-Applied Research Management, Astellas Pharma Inc., Tokyo, JapanImmuno-Oncology, Astellas Pharma Inc., Tsukuba, JapanDepartment of Otolaryngology-Head and Neck surgery, Asahikawa Medical University, Asahikawa, JapanDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United StatesIntroductionActivation of T cell receptor (TCR) signaling is critical for clonal expansion of CD8+ T cells. However, the effects of augmenting TCR signaling during chronic antigen exposure is less understood. Here, we investigated the role of diacylglycerol (DAG)-mediated signaling downstream of the TCR during chronic lymphocytic choriomeningitis virus clone 13 (LCMV CL13) infection by blocking DAG kinase zeta (DGKζ), a negative regulator of DAG.MethodsWe examined the activation, survival, expansion, and phenotype of virus-specific T cell in the acute and chronic phases of LCMV CL13-infected in mice after DGKζ blockade or selective activation of ERK.ResultsUpon LCMV CL13 infection, DGKζ deficiency promoted early short-lived effector cell (SLEC) differentiation of LCMV-specific CD8+ T cells, but this was followed by abrupt cell death. Short-term inhibition of DGKζ with ASP1570, a DGKζ-selective pharmacological inhibitor, augmented CD8+ T cell activation without causing cell death, which reduced virus titers both in the acute and chronic phases of LCMV CL13 infection. Unexpectedly, the selective enhancement of ERK, one key signaling pathway downstream of DAG, lowered viral titers and promoted expansion, survival, and a memory phenotype of LCMV-specific CD8+ T cells in the acute phase with fewer exhausted T cells in the chronic phase. The difference seen between DGKζ deficiency and selective ERK enhancement could be potentially explained by the activation of the AKT/mTOR pathway by DGKζ deficiency, since the mTOR inhibitor rapamycin rescued the abrupt cell death seen in virus-specific DGKζ KO CD8+ T cells.DiscussionThus, while ERK is downstream of DAG signaling, the two pathways lead to distinct outcomes in the context of chronic CD8+ T cell activation, whereby DAG promotes SLEC differentiation and ERK promotes a memory phenotype.https://www.frontiersin.org/articles/10.3389/fimmu.2022.1032113/fullTCR T cell receptordiacylglycerol kinase (DGK)ERK (extracellular signal-regulated kinase)chronic viral infectionT cell exhaustion |
| spellingShingle | Shohei Harabuchi Shohei Harabuchi Omar Khan Hamid Bassiri Taku Yoshida Yohei Okada Masaomi Takizawa Osamu Ikeda Akihiro Katada Taku Kambayashi Manipulation of diacylglycerol and ERK-mediated signaling differentially controls CD8+ T cell responses during chronic viral infection Frontiers in Immunology TCR T cell receptor diacylglycerol kinase (DGK) ERK (extracellular signal-regulated kinase) chronic viral infection T cell exhaustion |
| title | Manipulation of diacylglycerol and ERK-mediated signaling differentially controls CD8+ T cell responses during chronic viral infection |
| title_full | Manipulation of diacylglycerol and ERK-mediated signaling differentially controls CD8+ T cell responses during chronic viral infection |
| title_fullStr | Manipulation of diacylglycerol and ERK-mediated signaling differentially controls CD8+ T cell responses during chronic viral infection |
| title_full_unstemmed | Manipulation of diacylglycerol and ERK-mediated signaling differentially controls CD8+ T cell responses during chronic viral infection |
| title_short | Manipulation of diacylglycerol and ERK-mediated signaling differentially controls CD8+ T cell responses during chronic viral infection |
| title_sort | manipulation of diacylglycerol and erk mediated signaling differentially controls cd8 t cell responses during chronic viral infection |
| topic | TCR T cell receptor diacylglycerol kinase (DGK) ERK (extracellular signal-regulated kinase) chronic viral infection T cell exhaustion |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.1032113/full |
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