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 8

c-Rel regulates the expression of a restricted set of genes at early stages of CD4+ T cell activation.

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c-Rel regulates the expression of a restricted set of genes at early sta...
(A) Heatmap showing log2 FC of expression in PMA-stimulated naive CD4+ T cell at 2 hours. Only genes both differentially expressed in response to stimulation in controls (adjusted P < 0.05 and | log2 FC | >1) and differentially expressed in P (adjusted P < 0.05 and | log2 FC | >2) are shown. For selected genes, the log2 FC between controls and P is indicated. (B) DNA binding motifs at PMA-induced c-Rel binding peaks. The de novo motif discovery P value and family of transcription factors are shown. (C) Bubble histogram showing the association of P’s dysregulated genes with c-Rel genomic binding sites as defined by ChIP-Seq in PMA-stimulated naive CD4+ T cells and located within 10 kb of their transcription start site. The association was computed for all c-Rel peaks and for a subgroup of peaks for which c-Rel binding increased by more than 5-fold following stimulation (1309 peaks). The circle size represents the significance of the association (–log10 Fisher’s exact test P value). The color gradient shows the ratio of the number of peaks proximal (within 10 kb) to these genes relative to randomly selected gene sets. (D) Genomic snapshots of selected genes with lower levels of expression in P. The top 3 tracks show the control input DNA and ChIP-Seq for c-Rel in nonstimulated (NS) and PMA-treated naive CD4+ T cells from 3 controls; blue boxes indicate significant c-Rel binding peaks. Below the gene structure are shown the normalized RNA-Seq profiles for naive CD4+ T cells from controls (overlaid) and P, at steady state or after stimulation. (E) RT-qPCR after 2 hours of activation of naive CD4+ T cells from 4 controls and P with anti-CD3 mAb with or without anti-CD28 mAb. Data are displayed as 2-ΔCt after normalization to GUS expression. Error bars represent the SD. n = 1.