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

J Clin Invest. 2021 Sep 1;131(17):e150143. doi: 10.1172/JCI150143.


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.

Keywords: Genetic diseases; Genetics; Immunology.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity / genetics
  • Adaptive Immunity / immunology
  • Child
  • Consanguinity
  • Female
  • Genes, rel*
  • Hematopoietic Stem Cell Transplantation
  • Homozygote
  • Host Microbial Interactions / genetics
  • Host Microbial Interactions / immunology
  • Humans
  • Immunity, Innate / genetics
  • Immunity, Innate / immunology
  • Lymphocyte Activation
  • Lymphocytes / classification
  • Lymphocytes / immunology
  • Mutation
  • Myeloid Cells / immunology
  • Primary Immunodeficiency Diseases / genetics*
  • Primary Immunodeficiency Diseases / immunology*
  • Primary Immunodeficiency Diseases / therapy
  • Protein Isoforms
  • Proto-Oncogene Proteins c-rel / deficiency*
  • Proto-Oncogene Proteins c-rel / genetics*


  • Protein Isoforms
  • Proto-Oncogene Proteins c-rel
  • REL protein, human