# Immune dysregulation from a novel CTLA-4 haploinsufficiency variant

## TL;DR

A new mutation in the CTLA-4 gene causes immune problems by reducing the protein's stability and function, leading to autoimmunity and infections.

## Contribution

A novel CTLA-4 variant is identified that causes immune dysregulation through haploinsufficiency and impaired transendocytosis.

## Key findings

- The p.Tyr218* variant truncates the cytoplasmic tail of CTLA-4, reducing its stability and transendocytosis.
- Patient T cells showed reduced CTLA-4 expression, and Jurkat cells with the variant had increased protein degradation.
- The C-terminal domain of CTLA-4 is critical for immune homeostasis and ligand uptake.

## Abstract

We describe a novel CTLA-4 p.Tyr218* variant associated with immune dysregulation across four generations. The mutation truncates the cytoplasmic tail, reducing CTLA-4 stability and transendocytosis, consistent with haploinsufficiency and autoimmunity. These findings suggest an important role for the C-terminal domain of CTLA-4 in maintaining immune homeostasis.

Cytotoxic T lymphocyte antigen 4 (CTLA-4) is a key immune checkpoint receptor that regulates T cell activation through ligand competition and transendocytosis. Heterozygous loss-of-function variants in CTLA4 result in CTLA-4 haploinsufficiency with autoimmune infiltration (CHAI), characterized by immune dysregulation and autoimmunity. We report a multigenerational family carrying a novel heterozygous CTLA4 variant, c.654T>A (p.Tyr218*), which truncates the cytoplasmic tail. Affected individuals presented with recurrent infections and autoimmune manifestations. Patient T cells showed reduced CTLA-4 expression at baseline and after stimulation, suggesting impaired stability. Jurkat cells expressing CTLA-4 Y218* exhibited enhanced degradation, partially rescued by lysosomal inhibition, and reduced transendocytosis of CD80. Together, these findings suggest that the CTLA-4 p.Tyr218* variant compromises protein stability and ligand uptake, contributing to CTLA-4 haploinsufficiency and immune dysregulation. This work broadens the spectrum of CTLA4 variants and underscores the importance of the C-terminal cytoplasmic domain in CTLA-4 function and immune regulation.