Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents Journal Article
| Authors: | Lévy, R.; Langlais, D.; Béziat, 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. |
| Article Title: | 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. © 2021, American Society for Clinical Investigation. |
| Keywords: | child; clinical article; protein expression; survival rate; human cell; case report; cd8+ t lymphocyte; lymphocyte proliferation; cell survival; interleukin 2; bim protein; immunoglobulin; herpes zoster; regulatory t lymphocyte; myc protein; cd4+ t lymphocyte; natural killer cell; cytokine production; effector cell; bone marrow cell; th1 cell; monocyte; memory cell; loss of function mutation; cytomegalovirus infection; antigen presenting cell; interleukin 12; lymphocyte count; tuberculosis; cd86 antigen; cd45ra antigen; b lymphocyte differentiation; memory t lymphocyte; cryptosporidiosis; lymphoid cell; microbial immunity; interleukin 23; transcription factor rel; human; article; infectious agent; mucocutaneous candidiasis; plasmablast |
| Journal Title: | Journal of Clinical Investigation |
| Volume: | 131 |
| Issue: | 17 |
| ISSN: | 0021-9738 |
| Publisher: | American Society for Clinical Investigation |
| Date Published: | 2021-09-01 |
| Start Page: | e150143 |
| Language: | English |
| DOI: | 10.1172/jci150143 |
| PROVIDER: | scopus |
| PMCID: | PMC8409595 |
| PUBMED: | 34623332 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 October 2021 -- Source: Scopus |
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