Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents
Romain Lévy, … , Jean-Laurent Casanova, Anne Puel
Romain Lévy, … , Jean-Laurent Casanova, Anne Puel
Published September 1, 2021
Citation Information: J Clin Invest. 2021;131(17):e150143. https://doi.org/10.1172/JCI150143.
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Research Article Genetics Immunology

Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents

Abstract

We studied a child with severe viral, bacterial, fungal, and parasitic diseases, who was homozygous for a loss-of-function mutation of REL, encoding c-Rel, which is selectively expressed in lymphoid and myeloid cells. The patient had low frequencies of NK, effector memory cells reexpressing CD45RA (Temra) CD8+ T cells, memory CD4+ T cells, including Th1 and Th1*, Tregs, and memory B cells, whereas the counts and proportions of other leukocyte subsets were normal. Functional deficits of myeloid cells included the abolition of IL-12 and IL-23 production by conventional DC1s (cDC1s) and monocytes, but not cDC2s. c-Rel was also required for induction of CD86 expression on, and thus antigen-presenting cell function of, cDCs. Functional deficits of lymphoid cells included reduced IL-2 production by naive T cells, correlating with low proliferation and survival rates and poor production of Th1, Th2, and Th17 cytokines by memory CD4+ T cells. In naive CD4+ T cells, c-Rel is dispensable for early IL2 induction but contributes to later phases of IL2 expression. The patient’s naive B cells displayed impaired MYC and BCL2L1 induction, compromising B cell survival and proliferation and preventing their differentiation into Ig-secreting plasmablasts. Inherited c-Rel deficiency disrupts the development and function of multiple myeloid and lymphoid cells, compromising innate and adaptive immunity to multiple infectious agents.

Authors

Romain Lévy, David Langlais, Vivien Béziat, Franck Rapaport, Geetha Rao, Tomi Lazarov, Mathieu Bourgey, Yu J. Zhou, Coralie Briand, Kunihiko Moriya, Fatima Ailal, Danielle T. Avery, Janet Markle, Ai Ing Lim, Masato Ogishi, Rui Yang, Simon Pelham, Mehdi Emam, Mélanie Migaud, Caroline Deswarte, Tanwir Habib, Luis R. Saraiva, Eman A. Moussa, Andrea Guennoun, Bertrand Boisson, Serkan Belkaya, Ruben Martinez-Barricarte, Jérémie Rosain, Aziz Belkadi, Sylvain Breton, Kathryn Payne, Ibtihal Benhsaien, Alessandro Plebani, Vassilios Lougaris, James P. Di Santo, Bénédicte Neven, Laurent Abel, Cindy S. Ma, Ahmed Aziz Bousfiha, Nico Marr, Jacinta Bustamante, Kang Liu, Philippe Gros, Frédéric Geissmann, Stuart G. Tangye, Jean-Laurent Casanova, Anne Puel

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Figure 2

An aberrant transcript underlies a loss of c-Rel production and function.

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An aberrant transcript underlies a loss of c-Rel production and function...
(A) PCR of full-length REL cDNA from EBV-B cells, showing a deletion of 14 nucleotides (r.395_408del) in exon 5 in P and a predicted termination codon (p.Val132Alafs*3). (B) RT-qPCR on total mRNA extracted from EBV-B cells from 3 controls (Ctls) and P. Data are displayed as 2-ΔCt after normalization to GUS expression. Data indicate the mean ± SEM. n = 3. (C) Western blot of extracts from HEK293T cells transfected with a pcDNA3.1 plasmid encoding an empty N-terminal DDK tag (empty vector [EV]), or encoding the WT or mutant (c.395_408del) REL allele. Two Abs were used: an Ab against the DDK tag and an Ab against GAPDH. Results are representative of 3 independent experiments. (D) Top panel: Luciferase activity of HEK293T cells cotransfected with an NF-κB reporter plasmid plus the pcDNA3.1 EV and a plasmid encoding the WT or c.395_408del REL allele. Results show the fold induction of activity relative to EV-transfected cells. Data indicate the mean ± SEM. n = 2. Each dot represents the mean of 9 technical replicates. Bottom panel: RT-qPCR results. Data are displayed as 2-ΔCt after normalization to GUS expression. Data indicate the mean ± SEM. n = 1. Each dot represents the mean of 3 technical replicates.