Cell-Intrinsic CD38 Expression Sustains Exhausted CD8+ T Cells by Regulating Their Survival and Metabolism during Chronic Viral Infection
Acute and chronic viral infections result in the differentiation of effector and exhausted T cells with functional and phenotypic differences that dictate whether the infection is cleared or progresses to chronicity. High CD38 expression has been observed on CD8+ T cells across various viral infections and tumors in patients, suggesting an important regulatory function for CD38 on responding T cells. Here, we show that CD38 expression was increased and sustained on exhausted CD8+ T cells following chronic lymphocytic choriomeningitis virus (LCMV) infection, with lower levels observed on T cells from acute LCMV infection. We uncovered a cell-intrinsic role for CD38 expression in regulating the survival of effector and exhausted CD8+ T cells. We observed increased proliferation and function of Cd38-/- CD8+ progenitor exhausted T cells compared to those of wild-type (WT) cells. Furthermore, decreased oxidative phosphorylation and glycolytic potential were observed in Cd38-/- CD8+ T cells during chronic but not acute LCMV infection. Our studies reveal that CD38 has a dual cell-intrinsic function in CD8+ T cells, where it decreases proliferation and function yet supports their survival and metabolism. These findings show that CD38 is not only a marker of T cell activation but also has regulatory functions on effector and exhausted CD8+ T cells. IMPORTANCE Our study shows how CD38 expression is regulated on CD8+ T cells responding during acute and chronic viral infection. We observed higher CD38 levels on CD8+ T cells during chronic viral infection compared to levels during acute viral infection. Deleting CD38 had an important cell-intrinsic function in ensuring the survival of virus-specific CD8+ T cells throughout the course of viral infection. We found defective metabolism in Cd38-/- CD8+ T cells arising during chronic infection and changes in their progenitor T cell phenotype. Our studies revealed a dual cell-intrinsic role for CD38 in limiting proliferation and granzyme B production in virus-specific exhausted T cells while also promoting their survival. These data highlight new avenues for research into the mechanisms through which CD38 regulates the survival and metabolism of CD8+ T cell responses to viral infections.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:97 |
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| Enthalten in: |
Journal of virology - 97(2023), 4 vom: 27. Apr., Seite e0022523 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
DeRogatis, Julia M [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 19.05.2023 Date Revised 20.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1128/jvi.00225-23 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a DeRogatis, Julia M |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Cell-Intrinsic CD38 Expression Sustains Exhausted CD8+ T Cells by Regulating Their Survival and Metabolism during Chronic Viral Infection |
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| 520 | |a Acute and chronic viral infections result in the differentiation of effector and exhausted T cells with functional and phenotypic differences that dictate whether the infection is cleared or progresses to chronicity. High CD38 expression has been observed on CD8+ T cells across various viral infections and tumors in patients, suggesting an important regulatory function for CD38 on responding T cells. Here, we show that CD38 expression was increased and sustained on exhausted CD8+ T cells following chronic lymphocytic choriomeningitis virus (LCMV) infection, with lower levels observed on T cells from acute LCMV infection. We uncovered a cell-intrinsic role for CD38 expression in regulating the survival of effector and exhausted CD8+ T cells. We observed increased proliferation and function of Cd38-/- CD8+ progenitor exhausted T cells compared to those of wild-type (WT) cells. Furthermore, decreased oxidative phosphorylation and glycolytic potential were observed in Cd38-/- CD8+ T cells during chronic but not acute LCMV infection. Our studies reveal that CD38 has a dual cell-intrinsic function in CD8+ T cells, where it decreases proliferation and function yet supports their survival and metabolism. These findings show that CD38 is not only a marker of T cell activation but also has regulatory functions on effector and exhausted CD8+ T cells. IMPORTANCE Our study shows how CD38 expression is regulated on CD8+ T cells responding during acute and chronic viral infection. We observed higher CD38 levels on CD8+ T cells during chronic viral infection compared to levels during acute viral infection. Deleting CD38 had an important cell-intrinsic function in ensuring the survival of virus-specific CD8+ T cells throughout the course of viral infection. We found defective metabolism in Cd38-/- CD8+ T cells arising during chronic infection and changes in their progenitor T cell phenotype. Our studies revealed a dual cell-intrinsic role for CD38 in limiting proliferation and granzyme B production in virus-specific exhausted T cells while also promoting their survival. These data highlight new avenues for research into the mechanisms through which CD38 regulates the survival and metabolism of CD8+ T cell responses to viral infections | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
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| 650 | 4 | |a T cell exhaustion | |
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| 650 | 4 | |a metabolism | |
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| 700 | 1 | |a Neubert, Emily N |e verfasserin |4 aut | |
| 700 | 1 | |a Viramontes, Karla M |e verfasserin |4 aut | |
| 700 | 1 | |a Henriquez, Monique L |e verfasserin |4 aut | |
| 700 | 1 | |a Nicholas, Dequina A |e verfasserin |4 aut | |
| 700 | 1 | |a Tinoco, Roberto |e verfasserin |4 aut | |
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