Ecto-NTPDase CD39 is a negative checkpoint that inhibits follicular helper cell generation
| Autor: | Xuanying Li, Fengqin Fang, Jörg J. Goronzy, Timothy M. Gould, Simon Lambert, Chulwoo Kim, Cornelia M. Weyand, Wenqiang Cao, Claire E. Gustafson |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Adenosine A2A receptor Mice Transgenic Biology Gene Expression Regulation Enzymologic 03 medical and health sciences Mice 0302 clinical medicine medicine Animals Humans Transcription factor Apyrase Germinal center Cell Differentiation General Medicine T-Lymphocytes Helper-Inducer Purinergic signalling BCL6 Acquired immune system Germinal Center Adenosine 030104 developmental biology 030220 oncology & carcinogenesis biology.protein Cancer research Antibody medicine.drug Signal Transduction Research Article |
| Zdroj: | J Clin Invest |
| ISSN: | 1558-8238 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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