Essential cell-extrinsic requirement for PDIA6 in lymphoid and myeloid development

J Exp Med. 2020 Apr 6;217(4):e20190006. doi: 10.1084/jem.20190006.


In a forward genetic screen of N-ethyl-N-nitrosourea (ENU)-induced mutant mice for aberrant immune function, we identified mice with a syndromic disorder marked by growth retardation, diabetes, premature death, and severe lymphoid and myeloid hypoplasia together with diminished T cell-independent (TI) antibody responses. The causative mutation was in Pdia6, an essential gene encoding protein disulfide isomerase A6 (PDIA6), an oxidoreductase that functions in nascent protein folding in the endoplasmic reticulum. The immune deficiency caused by the Pdia6 mutation was, with the exception of a residual T cell developmental defect, completely rescued in irradiated wild-type recipients of PDIA6-deficient bone marrow cells, both in the absence or presence of competition. The viable hypomorphic allele uncovered in these studies reveals an essential role for PDIA6 in hematopoiesis, but one extrinsic to cells of the hematopoietic lineage. We show evidence that this role is in the proper folding of Wnt3a, BAFF, IL-7, and perhaps other factors produced by the extra-hematopoietic compartment that contribute to the development and lineage commitment of hematopoietic cells.

MeSH terms

  • Animals
  • B-Cell Activating Factor / immunology
  • Cell Line
  • Female
  • HEK293 Cells
  • Hematopoiesis / immunology
  • Humans
  • Interleukin-7 / immunology
  • Lymphocytes / immunology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Myeloid Cells / immunology*
  • Protein Disulfide-Isomerases / immunology*
  • T-Lymphocytes / immunology
  • Wnt3A Protein / immunology


  • B-Cell Activating Factor
  • Interleukin-7
  • Wnt3A Protein
  • Pdia6 protein, mouse
  • Protein Disulfide-Isomerases