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 5

c-Rel deficiency affects the production of IL-12 and IFN-γ.

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c-Rel deficiency affects the production of IL-12 and IFN-γ. (A) ELISA re...
(A) ELISA results for IL-12p70 and IFN-γ production in whole blood from controls (n = 10) and P, after a 48-hour incubation with different ligands. Data indicate the mean ± SEM. n = 3. iono, ionomycin. (B) ELISA results showing IL-12p70 and TNF production in P’s EBV-B cells that were not transfected (NT), or transfected with an empty retroviral plasmid (EV) or a plasmid encoding the WT c-Rel (WT); in cells from patients with complete AR IL-12p40 deficiency (p40–/–, n = 2); and in cells from controls (n = 3), after a 24-hour incubation with PDBu (10–7 M) or PMA (400 ng/mL). Data indicate the mean ± SEM. n = 3. (C–E) IFN-γ expression after 24 hours of stimulation of leukocytes from 11 controls, 1 patient with AR IL-12Rβ1 deficiency, and P. (C) UMAP plots are presented with legends indicating the different leukocyte subsets, as defined by surface markers (indicated in Methods). (D) UMAP plots show Tbet and IFN-γ expression in leukocyte subsets from 2 representative controls, 1 patient with AR IL-12Rβ1 deficiency, and P. (E) Dot plot graphs are shown with the values obtained in D. Error bars represent the mean and SD. Technical replicates are shown for P.