In 1996, the cytotoxic T-lymphocyte antigen-4 gene (CTLA-4) encoded on chromosome 2q33 was identified as a further type 1 diabetes susceptibility gene. CTLA-4 is a surface molecule found on activated T cells which produces a negative signal by inhibiting the T cell receptor signaling complex ligand interactions (blocks binding of CD80 and CD86). Two major splice forms exist – encoding membrane bound and soluble forms. When CTLA-4 is knocked out, lymphoproliferative disorders result. An A49G polymorphism in exon 1 of CTLA-4 changes the amino acid sequence resulting in reduced cell surface expression. It is thought that inherited changes in CTLA-4 gene expression can increase T cell self-reactivity and therefore play an important role in autoimmune diseases such as type 1 diabetes.