Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4

Hye Sun Kuehn, Weiming Ouyang, Bernice Lo, Elissa K. Deenick, Julie E. Niemela, Danielle T. Avery, Jean Nicolas Schickel, Dat Q. Tran, Jennifer Stoddard, Yu Zhang, David M. Frucht, Bogdan Dumitriu, Phillip Scheinberg, Les R. Folio, Cathleen A. Frein, Susan Price, Christopher Koh, Theo Heller, Christine M. Seroogy, Anna HuttenlocherV. Koneti Rao, Helen C. Su, David Kleiner, Luigi D. Notarangelo, Yajesh Rampertaap, Kenneth N. Olivier, Joshua McElwee, Jason Hughes, Stefania Pittaluga, Joao B. Oliveira, Eric Meffre, Thomas A. Fleisher, Steven M. Holland, Michael J. Lenardo, Stuart G. Tangye, Gulbu Uzel

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374 Citations (Scopus)


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 CD21loB 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.

Original languageEnglish
Pages (from-to)1623-1627
Number of pages5
Issue number6204
Publication statusPublished - 26 Sep 2014
Externally publishedYes


ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

Kuehn, H. S., Ouyang, W., Lo, B., Deenick, E. K., Niemela, J. E., Avery, D. T., Schickel, J. N., Tran, D. Q., Stoddard, J., Zhang, Y., Frucht, D. M., Dumitriu, B., Scheinberg, P., Folio, L. R., Frein, C. A., Price, S., Koh, C., Heller, T., Seroogy, C. M., ... Uzel, G. (2014). Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science, 345(6204), 1623-1627.