Journal
BLOOD
Volume 129, Issue 11, Pages 1458-1468Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2016-10-745174
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Funding
- National Institute for Health Research (NIHR) Rare Diseases Translational Research Collaboration via the NIHR University College London Hospitals Biomedical Research Centre
- NIHR
- Biotechnology and Biological Sciences Research Council (BBSRC)
- Wellcome Trust Clinical PhD Studentship.
- Great Ormond St. Biomedical Research Centre.
- BBSRC [BB/M009203/1] Funding Source: UKRI
- MRC [MR/N001435/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/M009203/1, 1497411] Funding Source: researchfish
- Medical Research Council [MR/N001435/1] Funding Source: researchfish
- National Institute for Health Research [RP-2014-05-007] Funding Source: researchfish
- The Sir Jules Thorn Charitable Trust [12JTA] Funding Source: researchfish
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Heterozygous CTLA-4 deficiency has been reported as a monogenic cause of common variable immune deficiency with features of immune dysregulation. Direct mutation in CTLA-4 leads to defective regulatory T- cell (Treg) 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(-)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.
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