Dual T cell- and B cell-intrinsic deficiency in humans with biallelic RLTPR mutations

J Exp Med. 2016 Oct 17;213(11):2413-2435. doi: 10.1084/jem.20160576. Epub 2016 Sep 19.


Combined immunodeficiency (CID) refers to inborn errors of human T cells that also affect B cells because of the T cell deficit or an additional B cell-intrinsic deficit. In this study, we report six patients from three unrelated families with biallelic loss-of-function mutations in RLTPR, the mouse orthologue of which is essential for CD28 signaling. The patients have cutaneous and pulmonary allergy, as well as a variety of bacterial and fungal infectious diseases, including invasive tuberculosis and mucocutaneous candidiasis. Proportions of circulating regulatory T cells and memory CD4+ T cells are reduced. Their CD4+ T cells do not respond to CD28 stimulation. Their CD4+ T cells exhibit a "Th2" cell bias ex vivo and when cultured in vitro, contrasting with the paucity of "Th1," "Th17," and T follicular helper cells. The patients also display few memory B cells and poor antibody responses. This B cell phenotype does not result solely from the T cell deficiency, as the patients' B cells fail to activate NF-κB upon B cell receptor (BCR) stimulation. Human RLTPR deficiency is a CID affecting at least the CD28-responsive pathway in T cells and the BCR-responsive pathway in B cells.

MeSH terms

  • Adolescent
  • Adult
  • Alleles*
  • B-Lymphocytes / immunology*
  • Base Sequence
  • CD28 Antigens / metabolism
  • CD4-Positive T-Lymphocytes / immunology
  • Cell Differentiation / genetics
  • Cell Proliferation / genetics
  • Cell Survival / genetics
  • Child
  • Child, Preschool
  • Dimerization
  • Female
  • HEK293 Cells
  • Humans
  • Immunologic Memory
  • Immunophenotyping
  • Leukocytes / pathology
  • Male
  • Microfilament Proteins / genetics*
  • Mutation / genetics*
  • NF-kappa B / metabolism
  • Pedigree
  • Phenotype
  • Receptors, Antigen, B-Cell
  • Signal Transduction
  • T-Lymphocytes / immunology*
  • Th17 Cells / immunology
  • Th2 Cells / immunology
  • Young Adult


  • CARMIL1 protein, human
  • CD28 Antigens
  • Microfilament Proteins
  • NF-kappa B
  • Receptors, Antigen, B-Cell