Helpless Priming Sends CD8+ T Cells on the Road to Exhaustion
Persistent antigen exposure in chronic infection and cancer has been proposed to lead to cytotoxic T lymphocyte (CTL) “exhaustion”, i.e., loss of effector function and disease control. Recent work identifies a population of poorly differentiated TCF-1+PD-1+ CD8+ T cells as precursors of the terminal...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-10-01
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| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2020.592569/full |
| _version_ | 1818108420251713536 |
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| author | Julia Busselaar Sun Tian Hans van Eenennaam Jannie Borst |
| author_facet | Julia Busselaar Sun Tian Hans van Eenennaam Jannie Borst |
| author_sort | Julia Busselaar |
| collection | DOAJ |
| description | Persistent antigen exposure in chronic infection and cancer has been proposed to lead to cytotoxic T lymphocyte (CTL) “exhaustion”, i.e., loss of effector function and disease control. Recent work identifies a population of poorly differentiated TCF-1+PD-1+ CD8+ T cells as precursors of the terminally exhausted CTL pool. These “predysfunctional” CTLs are suggested to respond to PD-1 targeted therapy by giving rise to a pool of functional CTLs. Supported by gene expression analyses, we present a model in which lack of CD4+ T cell help during CD8+ T cell priming results in the formation of predysfunctional CTLs. Our model implies that predysfunctional CTLs are formed during priming and that the remedy for CTL dysfunction is to provide “help” signals for generation of optimal CTL effectors. We substantiate that this may be achieved by engaging CD4+ T cells in new CD8+ T cell priming, or by combined PD-1 blocking and CD27 agonism with available immunotherapeutic antibodies. |
| first_indexed | 2024-12-11T02:15:04Z |
| format | Article |
| id | doaj.art-01e4c58a73e045768e15e740f92a1582 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-11T02:15:04Z |
| publishDate | 2020-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-01e4c58a73e045768e15e740f92a15822022-12-22T01:24:12ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-10-011110.3389/fimmu.2020.592569592569Helpless Priming Sends CD8+ T Cells on the Road to ExhaustionJulia Busselaar0Sun Tian1Hans van Eenennaam2Jannie Borst3Department of Immunology and Oncode Institute, Leiden University Medical Center, Leiden, NetherlandsAduro Biotech Europe BV, Oss, NetherlandsAIMM Therapeutics BV, Amsterdam, NetherlandsDepartment of Immunology and Oncode Institute, Leiden University Medical Center, Leiden, NetherlandsPersistent antigen exposure in chronic infection and cancer has been proposed to lead to cytotoxic T lymphocyte (CTL) “exhaustion”, i.e., loss of effector function and disease control. Recent work identifies a population of poorly differentiated TCF-1+PD-1+ CD8+ T cells as precursors of the terminally exhausted CTL pool. These “predysfunctional” CTLs are suggested to respond to PD-1 targeted therapy by giving rise to a pool of functional CTLs. Supported by gene expression analyses, we present a model in which lack of CD4+ T cell help during CD8+ T cell priming results in the formation of predysfunctional CTLs. Our model implies that predysfunctional CTLs are formed during priming and that the remedy for CTL dysfunction is to provide “help” signals for generation of optimal CTL effectors. We substantiate that this may be achieved by engaging CD4+ T cells in new CD8+ T cell priming, or by combined PD-1 blocking and CD27 agonism with available immunotherapeutic antibodies.https://www.frontiersin.org/article/10.3389/fimmu.2020.592569/fullCD8+ T cellCD4+ T cellexhaustiondysfunctioncancerinfection |
| spellingShingle | Julia Busselaar Sun Tian Hans van Eenennaam Jannie Borst Helpless Priming Sends CD8+ T Cells on the Road to Exhaustion Frontiers in Immunology CD8+ T cell CD4+ T cell exhaustion dysfunction cancer infection |
| title | Helpless Priming Sends CD8+ T Cells on the Road to Exhaustion |
| title_full | Helpless Priming Sends CD8+ T Cells on the Road to Exhaustion |
| title_fullStr | Helpless Priming Sends CD8+ T Cells on the Road to Exhaustion |
| title_full_unstemmed | Helpless Priming Sends CD8+ T Cells on the Road to Exhaustion |
| title_short | Helpless Priming Sends CD8+ T Cells on the Road to Exhaustion |
| title_sort | helpless priming sends cd8 t cells on the road to exhaustion |
| topic | CD8+ T cell CD4+ T cell exhaustion dysfunction cancer infection |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2020.592569/full |
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