Identifying functional defects in patients with immune dysregulation due to LRBA and CTLA-4 mutations

Tie Zheng Hou, Nisha Verma, Jennifer Wanders, Alan Kennedy, Blagoje Soskic, Daniel Janman, Neil Halliday, Behzad Rowshanravan, Austen Worth, Waseem Qasim, Helen Baxendale, Hans Stauss, Suranjith Seneviratne, Olaf Neth, Peter Olbrich, Sophie Hambleton, Peter D Arkwright, Siobhan O Burns, Lucy S K Walker, David M Sansom

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Abstract

Heterozygous CTLA-4 deficiency has been reported as a monogenic cause of common variable immune deficiency (CVID) with features of immune dysregulation. Direct mutation in CTLA-4 leads to defective regulatory T cell function associated with impaired ability to control levels of the CTLA-4 ligands, CD80 and CD86. However, additional mutations affecting the CTLA-4 pathway, such as those recently reported for LRBA, indirectly affect CTLA-4 expression resulting in clinically similar disorders. Robust phenotyping approaches sensitive to defects in the CTLA-4 pathway are therefore required to inform understanding of such immune dysregulation syndromes. Here we describe assays capable of distinguishing a variety of defects in the CTLA-4 pathway. Assessing total CTLA-4 expression levels was found to be optimal when restricting analysis to the CD45RA-negative Foxp3+ fraction. CTLA-4 induction following stimulation, and the use of lysosomal blocking compounds, distinguished CTLA-4 from LRBA mutations. Short term T cell stimulation improved the capacity for discriminating the Foxp3+ Treg compartment, clearly revealing Treg expansions in these disorders. Finally, we developed a functionally orientated assay to measure ligand uptake by CTLA-4, which is sensitive to ligand-binding or trafficking mutations, that would otherwise be difficult to detect and that is appropriate for testing novel mutations in CTLA-4 pathway genes. These approaches are likely to be of value in interpreting the functional significance of mutations in the CTLA-4 pathway identified by gene sequencing approaches.

Original languageEnglish
JournalBlood
Early online date3 Feb 2017
DOIs
Publication statusPublished - 2017

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