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Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4


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 CD21(lo) 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.

Type Journal
Authors 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.; Huttenlocher, A.; Rao, V. K.; Su, H. C.; Kleiner, D.; Notarangelo, L. D.; Rampertaap, Y.; Olivier, K. N.; McElwee, J.; Hughes, J.; Pittaluga, S.; Oliveira, J. B.; Meffre, E.; Fleisher, T. A.; Holland, S. M.; Lenardo, M. J.; Tangye, S. G.; Uzel, G.
Publisher Name SCIENCE
Published Date 2014-11-20
Published Volume 345
Published Issue 6204
Published Pages 1623-7
Status Published in-print
DOI 10.1126/science.1255904
URL link to publisher's version
OpenAccess link to author's accepted manuscript version