Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4

• Published in: Science (American Association for the Advancement of Science) Vol. 345; no. 6204; pp. 1623 - 1627
• Main Authors: Sun Kuehn, Hye, Ouyang, Weiming, Lo, Bernice, Deenick, Elissa K., Niemela, Julie E., Avery, Danielle T., Schickel, Jean-Nicolas, Tran, Dat Q., Stoddard, Jennifer, Zhang, Yu, Frucht, David M., Dumitriu, Bogdan, Scheinberg, Phillip, Folio, Les R., Frein, Cathleen A., Price, Susan, Koh, Christopher, Heller, Theo, Seroogy, Christine M., Huttenlocher, Anna, Rao, V. Koneti, Su, Helen C., Kleiner, David, Notarangelo, Luigi D., Rampertaap, Yajesh, Olivier, Kenneth N., McElwee, Joshua, Hughes, Jason, Pittaluga, Stefania, Oliveira, Joao B., Meffre, Eric, Fleisher, Thomas A., Holland, Steven M., Lenardo, Michael J., Tangye, Stuart G., Uzel, Gulbu
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 26.09.2014; The American Association for the Advancement of Science
• Subjects: Adult; Animals; B-Lymphocytes - immunology; CTLA-4 Antigen - genetics; Female; Forkhead Transcription Factors - immunology; Genetics; Germ-Line Mutation; Government regulations; Haploinsufficiency; Humans; Immune system; Immune System Diseases - genetics; Immune systems; Immunity - genetics; Lymphocyte receptors; Lymphocytes; Male; Mice; Mice, Mutant Strains; Mutation; Mutations; Organs; Patients; Pedigree; Proteins; T-Lymphocytes, Regulatory - immunology; Young Adult
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.1255904

Cytotoxic T lymphocyte antigen–4 (CTLA-4) is an inhibitory receptor found on immune cells. The consequences of mutations in CTLA4 in humans are unknown. We identified germline heterozygous mutations in CTLA4 in subjects with severe immune dysregulation from four unrelated families. Whereas Ctla4 heterozygous mice have no obvious phenotype, human CTLA4 haploinsufficiency caused dysregulation of FoxP3⁺ regulatory T (Treg) cells, hyperactivation of effector T cells, and lymphocytic infiltration of target organs. Patients also exhibited progressive loss of circulating B cells, associated with an increase of predominantly autoreactive CD21lo B cells and accumulation of B cells in nonlymphoid organs. Inherited human CTLA4 haploinsufficiency demonstrates a critical quantitative role for CTLA-4 in governing T and B lymphocyte homeostasis.