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


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.

Type Journal
ISBN 1558-8238 (Electronic) 0021-9738 (Linking)
Authors Levy, R.; Langlais, D.; Beziat, V.; Rapaport, F.; Rao, G.; Lazarov, T.; Bourgey, M.; Zhou, Y. J.; Briand, C.; Moriya, K.; Ailal, F.; Avery, D. T.; Markle, J.; Lim, A. I.; Ogishi, M.; Yang, R.; Pelham, S.; Emam, M.; Migaud, M.; Deswarte, C.; Habib, T.; Saraiva, L. R.; Moussa, E. A.; Guennoun, A.; Boisson, B.; Belkaya, S.; Martinez-Barricarte, R.; Rosain, J.; Belkadi, A.; Breton, S.; Payne, K.; Benhsaien, I.; Plebani, A.; Lougaris, V.; Di Santo, J. P.; Neven, B.; Abel, L.; Ma, C. S.; Bousfiha, A. A.; Marr, N.; Bustamante, J.; Liu, K.; Gros, P.; Geissmann, F.; Tangye, S. G.; Casanova, J. L.; Puel, A.
Responsible Garvan Author Prof Stuart Tangye
Published Date 2021-09-30
Published Volume 131
Published Issue 17
Published Pages e150143
Status Published in-print
DOI 10.1172/JCI150143
URL link to publisher's version