Lost in Translation: Lack of CD4 Expression due to a Novel Genetic Defect

• Published in: The Journal of infectious diseases 2021-02, Vol.223 (4), p.645-654
• Main Authors: Lisco, Andrea, Ye, Peiying, Wong, Chun-Shu, Pei, Luxin, Hsu, Amy P, Mace, Emily M, Orange, Jordan S, Lage, Silvia Lucena, Ward, Addison Jon, Migueles, Stephen A, Connors, Mark, Anderson, Megan V, Buckner, Clarisa M, Moir, Susan, Rupert, Adam, Dulau-Florea, Alina, Ogbogu, Princess, Timberlake, Dylan, Notarangelo, Luigi D, Pittaluga, Stefania, Abraham, Roshini S, Sereti, Irini
• Format: Article
• Language: English
• Subjects: Bone marrow; Bone Marrow - immunology; Bone Marrow - metabolism; CD4 antigen; CD4 Antigens - analysis; CD4 Antigens - blood; CD4 Antigens - deficiency; CD4 Antigens - genetics; CD4-Positive T-Lymphocytes - immunology; CD8 antigen; Cell activation; Codon, Initiator; Cytokines - immunology; Cytokines - metabolism; Editor's Choice; Female; Humans; Ileum; Ileum - immunology; Ileum - metabolism; Immunity, Innate; Immunologic Deficiency Syndromes - genetics; Immunologic Deficiency Syndromes - immunology; Killer Cells, Natural - immunology; Lymph nodes; Lymph Nodes - immunology; Lymph Nodes - metabolism; Lymphocyte Activation; Lymphocytes B; Lymphocytes T; Major and Brief Reports; Male; Monocytes - immunology; Mutation, Missense; Pedigree; Peptide Chain Initiation, Translational - genetics; Peripheral blood; Primary Immunodeficiency Diseases - genetics; Primary Immunodeficiency Diseases - immunology; T-Lymphocyte Subsets - immunology; Translation; Translation initiation; Young Adult
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jiab025

Abstract CD4 expression identifies a subset of mature T cells primarily assisting the germinal center reaction and contributing to CD8+ T-cell and B-cell activation, functions, and longevity. Herein, we present a family in which a novel variant disrupting the translation-initiation codon of the CD4 gene resulted in complete loss of membrane and plasma soluble CD4 in peripheral blood, lymph node, bone marrow, skin, and ileum of a homozygous proband. This inherited CD4 knockout disease illustrates the clinical and immunological features of a complete deficiency of any functional component of CD4 and its similarities and differences with other clinical models of primary or acquired loss of CD4+ T cells. The first inherited loss of any functional component of CD4, including soluble-CD4, is clinically distinct from any other congenital or acquired CD4 T-cell defect and characterized by compensatory changes in T-cell subsets and functional impairment of B-cells, monocyte and NK-cells.