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

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

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 8

COX-2 inhibition enhances Tfh differentiation through repressing CD39.

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COX-2 inhibition enhances Tfh differentiation through repressing CD39. (...
(A–C) B6 mice infected with LMCV were treated with vehicle or celecoxib i.p. every other day. Splenocytes were analyzed on day 8. (A) CD39 expression on gated GP66-77 IAb tetramer+ CD4+ T cells. Frequencies of CXCR5hiSLAMlo (Tfh) and CXCR5loSLAMhi (Th1) CD4+ T cells (B) and PD-1+CXCR5+ GC Tfh (C) from 1 representative of 2 experiments with 3 mice in each group. (D) B6 mice were immunized with NP-OVA. Celecoxib was given every other day starting on day 1 after immunization and splenocytes were analyzed by flow cytometry on day 12: results from 4 or 5 mice in each group. (E and F) SMARTA CD4+ T cells transduced with the Entpd1 shRNAmir retrovirus were transferred into B6 mice. Mice were infected with LCMV and treated with celecoxib every other day. Splenocytes were analyzed on day 8 after LCMV infection. Frequencies of Tfh (CXCR5hiSLAMlo) and Th1 (SLAMhiCXCR5lo) (E) and GC Tfh (CXCR5+BCL6+) (F) are shown as percentage of SMARTA CD4+ T cells. (G) OT-II CD4+ T cells transduced with indicated retrovirus were transferred into CD4-knockout mice. Mice were immunized with NP-OVA in alum and treated with celecoxib every other day. Splenocytes were analyzed on day 12 after immunization. Frequencies of GC B cells (FAS+GL7+) are shown as percentage of B cells. Data are representative of 2 experiments with 5 mice in each group. All data are shown as mean ± SEM and were compared by 2-tailed unpaired t test. *P < 0.05, **P ≤ 0.01. NS, not significant.