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 7

c-Rel deficiency impairs CD4+ T cell proliferation, IL-2 production, and effector function.

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c-Rel deficiency impairs CD4+ T cell proliferation, IL-2 production, and...
(A) Fresh PBMCs from controls (results for 1 control are shown) and P were incubated for 4 days with beads coated with anti-CD3/anti-CD28 mAbs, anti-CD2/anti-CD3/anti-CD28 mAbs (Th0), or PHA (1 μg/mL) with or without IL-2. Histograms show CFSE dilution for CD4+ T cells. Representative results from 3 independent experiments are shown. (B) Fresh PBMCs from 4 controls and P were cultured for 6 hours with anti-CD3/anti-CD28 mAbs or PMA (20 ng/mL) and ionomycin (10–7 M) (P/I). The percentage of IL-2+ cells and MFI of IL-2 in CD4+ T cells are shown. (C) Sorted naive CD4+ T cells from controls (n = 4) and P were incubated for 4 days under Th0 conditions. Flow cytometric analyses of CFSE dilution were performed, and the percentage of cells in each division was analyzed. Data indicate the mean ± SEM. Representative results from 2 independent experiments are shown. (D) Percentage of IL-2+ cells, analyzed by flow cytometry, in sorted naive CD4+ T cells from controls (n = 11) and P, after 4 days culturing under Th0 conditions. Data indicate the mean ± SEM. n = 3. (E) Analysis of cytokine production by sorted naive CD4+ T cells cultured under Th0 or Th1- or Th17-polarizing conditions. Cells were obtained from 40 (Th1 culture) and 30 (Th17 culture) controls and P, and cytokine production was measured after 5 days. Data indicate the mean ± SEM. Representative results from 2 independent experiments are shown. (F and G) Cytokine production by sorted memory CD4+ T cells from controls (n = 32) and P was measured after 5 days of culturing under Th0 conditions. Data indicate the mean ± SEM. Representative results from 2 independent experiments are shown.