CTLA-4 haploinsufficiency leads to late-onset autoimmune pathology in mice.

In humans, the loss of function in a single copy of the CTLA4 gene leads to an immune disorder characterized by a spectrum of immunodeficient and autoimmune manifestations. To investigate the pathogenicity of CTLA-4 haploinsufficiency, we utilized a heterozygous mouse model carrying a patient-derived Y139C mutation. We found that young heterozygous mice exhibited lymphoproliferative features and an activated T cell phenotype, without displaying autoimmunity. Co-culture assays revealed impaired trans-endocytosis. Despite this dysfunction, they remained resistant to induced inflammation. With age, however, they eventually developed spontaneous autoimmune manifestations that were more pronounced than those in age-matched littermates. Mechanistically, systemic activation induced CTLA-4-independent compensatory pathways, allowing Tregs to retain suppressive activity. Our study confirmed the pathogenicity of the Y139C heterozygous mutation, providing supporting evidence for CTLA-4 haploinsufficiency. Moreover, these results revealed that compensatory mechanisms arise in response to compromised trans-endocytosis. Further exploration may offer insights into disease progression and support the development of therapeutic strategies.