Hou, Tie ZhengOlbrich, PeterSoto, Jose Manuel LucenaSanchez, BertaMoreno, Paula SanchezBorte, StephanStauss, Hans JBurns, Siobhan OWalker, Lucy S KPan-Hammarström, QiangHammarström, LennartSansom, David MNeth, Olaf2023-01-252023-01-252018-01-03http://hdl.handle.net/10668/11974The CTLA-4 checkpoint regulates the activation of T cells. Individuals with heterozygous mutations in CTLA-4 have a complex phenotype typically characterized by antibody deficiency alongside variable autoimmunity. Despite severe disease in some individuals, others remain largely unaffected with reasons for this variation unknown. We studied a large family carrying a single point mutation in CTLA-4 leading to an amino acid change R75W and compared both unaffected with affected individuals. We measured a variety of features pertaining to T cell and CTLA-4 biology and observed that at the cellular level there was complete penetrance of CTLA-4 mutations. Accordingly, unaffected individuals were indistinguishable from those with disease in terms of level of CTLA-4 expression, percentage of Treg, upregulation of CTLA-4 upon stimulation and proliferation of CD4 T cells. We conclude that the wide variation in disease phenotype is influenced by immune variation outside of CTLA-4 biology.enAutoimmunityCD28CTLA-4ImmunodeficiencyMutationRegulatory T cellsCD28 AntigensCTLA-4 AntigenDiarrheaFamily HealthFemaleHumansIntestinal DiseasesLymphocyte ActivationMaleMutation, MissensePedigreeSeverity of Illness IndexSignal TransductionT-LymphocytesT-Lymphocytes, Regulatoryresearch article29305966open access10.1016/j.clim.2018.01.0011521-7035https://discovery.ucl.ac.uk/10044102/1/Hou%20clean%20submission.pdf