Ecto-NTPDase CD39 is a negative checkpoint that inhibits follicular helper cell generation

Wenqiang Cao, Fengqin Fang, Timothy Gould, Xuanying Li, Chulwoo Kim, Claire Gustafson, Simon Lambert, Cornelia M. Weyand, Jörg J. Goronzy

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)3422-3436
Number of pages15
JournalJournal of Clinical Investigation
Volume130
Issue number7
DOIs
Publication statusPublished - 2020 Jul 1
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by the NIH (R01 AR042527, R01 HL117913, R01 AI108906, R01 HL142068, and P01 HL129941 to CMW, and R01 AI108891, R01 AG045779, U19 AI057266, and R01 AI129191 to JJG) and with resources and the use of facilities at the Palo Alto Veterans Administration Healthcare System. Tetramers were provided by the NIH Tetramer Core Facility sup- ported by contract HHSN272201300006C from the NIAID. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Publisher Copyright:
Copyright: © 2020, American Society for Clinical Investigation.

ASJC Scopus subject areas

  • General Medicine

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