The Road Less Taken: Less Appreciated Pathways for Manipulating CD8+ T Cell Exhaustion
Exhausted CD8+ T (Tex) cells are a distinct cell population that arise during persistent antigen exposure in the context of chronic infections and cancers. Although characterized by progressive loss of effector functions, high and sustained inhibitory receptor expression and distinct transcriptional...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-07-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.926714/full |
| _version_ | 1818469850698219520 |
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| author | Andrea C. Pichler Jennifer L. Cannons Pamela L. Schwartzberg Pamela L. Schwartzberg |
| author_facet | Andrea C. Pichler Jennifer L. Cannons Pamela L. Schwartzberg Pamela L. Schwartzberg |
| author_sort | Andrea C. Pichler |
| collection | DOAJ |
| description | Exhausted CD8+ T (Tex) cells are a distinct cell population that arise during persistent antigen exposure in the context of chronic infections and cancers. Although characterized by progressive loss of effector functions, high and sustained inhibitory receptor expression and distinct transcriptional and epigenetic programs, Tex cells are heterogeneous. Among these, a self-renewing TCF-1+ Tex population, having unique characteristics and the ability to respond to immune-checkpoint blockade, gives rise to TCF-1- terminally Tex cells. These TCF-1+ cells have stem cell-like properties similar to memory T cell populations, but the signals that regulate the developmental pathways and relationships among exhausted cell populations are still unclear. Here, we review our current understanding of Tex cell biology, and discuss some less appreciated molecules and pathways affecting T cell exhaustion. We highlight two co-stimulatory receptors, CD226 and CD137, and their role in inducing or restraining T cell exhaustion, as well as signaling pathways that may be amenable to pharmacological inhibition with a focus on Phosphoinositide-3 Kinase and IL-2 partial agonists. Finally, we discuss novel methods that may increase TCF-1+ populations and therefore improve immunotherapy responsiveness. Understanding features of and pathways to exhaustion has important implications for the success of immunotherapy, including checkpoint blockade and adoptive T-cell transfer therapies. |
| first_indexed | 2024-04-13T21:29:10Z |
| format | Article |
| id | doaj.art-de404e54c81543bb815902703c987024 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-13T21:29:10Z |
| publishDate | 2022-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-de404e54c81543bb815902703c9870242022-12-22T02:29:13ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-07-011310.3389/fimmu.2022.926714926714The Road Less Taken: Less Appreciated Pathways for Manipulating CD8+ T Cell ExhaustionAndrea C. Pichler0Jennifer L. Cannons1Pamela L. Schwartzberg2Pamela L. Schwartzberg3Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United StatesLaboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United StatesLaboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United StatesNational Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United StatesExhausted CD8+ T (Tex) cells are a distinct cell population that arise during persistent antigen exposure in the context of chronic infections and cancers. Although characterized by progressive loss of effector functions, high and sustained inhibitory receptor expression and distinct transcriptional and epigenetic programs, Tex cells are heterogeneous. Among these, a self-renewing TCF-1+ Tex population, having unique characteristics and the ability to respond to immune-checkpoint blockade, gives rise to TCF-1- terminally Tex cells. These TCF-1+ cells have stem cell-like properties similar to memory T cell populations, but the signals that regulate the developmental pathways and relationships among exhausted cell populations are still unclear. Here, we review our current understanding of Tex cell biology, and discuss some less appreciated molecules and pathways affecting T cell exhaustion. We highlight two co-stimulatory receptors, CD226 and CD137, and their role in inducing or restraining T cell exhaustion, as well as signaling pathways that may be amenable to pharmacological inhibition with a focus on Phosphoinositide-3 Kinase and IL-2 partial agonists. Finally, we discuss novel methods that may increase TCF-1+ populations and therefore improve immunotherapy responsiveness. Understanding features of and pathways to exhaustion has important implications for the success of immunotherapy, including checkpoint blockade and adoptive T-cell transfer therapies.https://www.frontiersin.org/articles/10.3389/fimmu.2022.926714/fullCD8+ T cell exhaustionCD226CD137TCF-1PI3 Kinase deltaIL-2 |
| spellingShingle | Andrea C. Pichler Jennifer L. Cannons Pamela L. Schwartzberg Pamela L. Schwartzberg The Road Less Taken: Less Appreciated Pathways for Manipulating CD8+ T Cell Exhaustion Frontiers in Immunology CD8+ T cell exhaustion CD226 CD137 TCF-1 PI3 Kinase delta IL-2 |
| title | The Road Less Taken: Less Appreciated Pathways for Manipulating CD8+ T Cell Exhaustion |
| title_full | The Road Less Taken: Less Appreciated Pathways for Manipulating CD8+ T Cell Exhaustion |
| title_fullStr | The Road Less Taken: Less Appreciated Pathways for Manipulating CD8+ T Cell Exhaustion |
| title_full_unstemmed | The Road Less Taken: Less Appreciated Pathways for Manipulating CD8+ T Cell Exhaustion |
| title_short | The Road Less Taken: Less Appreciated Pathways for Manipulating CD8+ T Cell Exhaustion |
| title_sort | road less taken less appreciated pathways for manipulating cd8 t cell exhaustion |
| topic | CD8+ T cell exhaustion CD226 CD137 TCF-1 PI3 Kinase delta IL-2 |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.926714/full |
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