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Ecto-NTPDase CD39 is a negative checkpoint that inhibits follicular helper cell generation
Wenqiang Cao, … , Cornelia M. Weyand, Jörg J. Goronzy
Wenqiang Cao, … , Cornelia M. Weyand, Jörg J. Goronzy
Published May 26, 2020
Citation Information: J Clin Invest. 2020;130(7):3422-3436. https://doi.org/10.1172/JCI132417.
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Research Article Aging Article has an altmetric score of 4

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

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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.

Authors

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

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Figure 1

Failure of Tfh cells to induce expression of CD39.

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Failure of Tfh cells to induce expression of CD39.
(A) CD39 expression i...
(A) CD39 expression in subsets of human peripheral blood CD4+CD25– T cells: representative contour plots. (B) CD39 expression on CD4+ T cell subsets in human tonsils; contour plots are representative of 3 samples. (C–E) SMARTA CD4+ T cells were transferred into B6 mice and analyzed 8 days after LCMV infection. CD39 expression was determined on Th1 (SLAMhiCXCR5lo) and Tfh (SLAMloCXCR5hi) SMARTA cells. Representative contour plot and histogram (C) and summary data from 1 experiment with 4 mice representative of 3 experiments; (D) data are shown as mean ± SEM. (E) Contour plots of Th1 or Tfh in gated CD39– and CD39+ SMARTA CD4+ cells. (F) Naive CD4 cells isolated from human PBMCs were activated with anti-CD3/anti-CD28 Dynabeads under nonpolarizing (Th0) or Th1- or Tfh-polarizing conditions; CD39 expression was assessed on day 5. (G) CD39– and CD39+ CD4+ T cells were isolated 5 days after stimulation with anti-CD3/anti-CD28 Dynabeads and profiled for the expression of selected transcription factors by qPCR. Data were compared by 2-tailed paired t test (D and G) or 1-way ANOVA with Tukey’s post hoc test (F). *P < 0.05; **P ≤ 0.01; ****P ≤ 0.0001.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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