University College London, UK
Dr Hou has completed his PhD at the age of 30 years from Birmingham University and postdoctoral studies from University College London School of Medicine. He has published more than 15 papers in reputed journals.
Common variable immunodeficiency (CVID) is a heterogeneous group of immunodeficiencies characterised by low immunoglobulin levels and recurrent infections, frequently accompanied by autoimmune complications. CTLA-4 is an essential immune regulator, which controls T cell activation and plays a critical role in Treg suppression. CTLA-4 acts by controlling the levels of CD28 signalling in T cells via competition for their shared ligands CD80 and CD86 on APCs. A major effect of this competition is to prevent the activation of self-reactive T cells and disruption leads to fatal autoimmunity in mice. Using whole exome and targeted sequencing approaches we have identified a number of individuals with heterozygous mutations in CTLA-4, including stop codon, splice-site and missense mutations. These mutations, albeit incompletely penetrant, were found in CVID patients and family members associated with severe autoimmunity. Characterisation of T cells from several patients as well as unaffected carriers revealed reduced CTLA-4 expression, which was clearly evident in CD4+Foxp3+ Treg. Two independent point mutations in the CTLA-4 extracellular domain were found to significantly reduce the ability to bind ligand and carry out transendocytosis. Consistent with murine data, individuals with CTLA-4 insufficiency were found to have expanded numbers of Foxp3-expressing Treg in their blood irrespective of disease status, which most likely reflects enhanced CD28 signalling in Treg. Nonetheless, Treg were functionally impaired when tested in suppression assays. Together, these data reveal that CTLA-4 insufficiency in humans is associated with altered Treg homeostasis and function, autoimmune dysregulation as well as B cell- and antibody deficits.