Ecto-NTPDase CD39 is a negative checkpoint that inhibits follicular helper cell generation
Vaccination is a mainstay in preventive medicine, reducing morbidity and mortality from infection, largely by generating pathogen-specific neutralizing antibodies. However, standard immunization strategies are insufficient with increasing age due to immunological impediments, including defects in T follicular helper (Tfh) cells. Here, we found that Tfh generation is inversely linked to the expression of the ecto-NTPDase CD39 that modifies purinergic signaling. The lineage-determining transcription factor BCL6 inhibited CD39 expression, while increased Tfh frequencies were found in individuals with a germline polymorphism preventing transcription of ENTPD1, encoding CD39. In in vitro human and in vivo mouse studies, Tfh generation and germinal center responses were enhanced by reducing CD39 expression through the inhibition of the cAMP/PKA/p-CREB pathway, or by blocking adenosine signaling downstream of CD39 using the selective adenosine A2a receptor antagonist istradefylline. Thus, purinergic signaling in differentiating T cells can be targeted to improve vaccine responses, in particular in older individuals who have increased CD39 expression.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:130 |
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| Enthalten in: |
The Journal of clinical investigation - 130(2020), 7 vom: 01. Juli, Seite 3422-3436 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Cao, Wenqiang [VerfasserIn] |
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| Links: |
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| Themen: |
Adaptive immunity |
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| Anmerkungen: |
Date Completed 02.02.2021 Date Revised 14.02.2024 published: Print Citation Status MEDLINE |
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| doi: |
10.1172/JCI132417 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM310349729 |
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| 245 | 1 | 0 | |a Ecto-NTPDase CD39 is a negative checkpoint that inhibits follicular helper cell generation |
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| 500 | |a Date Revised 14.02.2024 | ||
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Vaccination is a mainstay in preventive medicine, reducing morbidity and mortality from infection, largely by generating pathogen-specific neutralizing antibodies. However, standard immunization strategies are insufficient with increasing age due to immunological impediments, including defects in T follicular helper (Tfh) cells. Here, we found that Tfh generation is inversely linked to the expression of the ecto-NTPDase CD39 that modifies purinergic signaling. The lineage-determining transcription factor BCL6 inhibited CD39 expression, while increased Tfh frequencies were found in individuals with a germline polymorphism preventing transcription of ENTPD1, encoding CD39. In in vitro human and in vivo mouse studies, Tfh generation and germinal center responses were enhanced by reducing CD39 expression through the inhibition of the cAMP/PKA/p-CREB pathway, or by blocking adenosine signaling downstream of CD39 using the selective adenosine A2a receptor antagonist istradefylline. Thus, purinergic signaling in differentiating T cells can be targeted to improve vaccine responses, in particular in older individuals who have increased CD39 expression | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a Adaptive immunity | |
| 650 | 4 | |a Aging | |
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| 700 | 1 | |a Gould, Timothy |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Xuanying |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Chulwoo |e verfasserin |4 aut | |
| 700 | 1 | |a Gustafson, Claire |e verfasserin |4 aut | |
| 700 | 1 | |a Lambert, Simon |e verfasserin |4 aut | |
| 700 | 1 | |a Weyand, Cornelia M |e verfasserin |4 aut | |
| 700 | 1 | |a Goronzy, Jörg J |e verfasserin |4 aut | |
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