Overexpression of the CTLA-4 Isoform

CTLA-4 is a potent inhibitor of T cell activation, primarily upon binding to its costimulatory ligands (B7.1 and B7.2) expressed on APCs. However, variants of CTLA-4 can also function independently of B7 molecules. 1/4CTLA-4 is a highly conserved isoform encoded by exons 1 and 4 of the Ctla4 gene that lacks the ligand-binding and the transmembrane domains, and as yet, its function is not known. To investigate the function of 1/4CTLA-4, we generated transgenic (Tg) mice overexpressing this variant. Cytokine production by 1/4CTLA-4 Tg T cells was elevated compared with wild type T cells. The frequency of CD44 high memory T cells in 1/4CTLA-4 Tg mice was increased, and as the mice aged, the frequency further increased. 1/4CTLA-4 Tg mice >1 y old had increased expression of T cell activation markers and developed spontaneous autoimmunity, including elevated production of autoantibodies. In contrast with young 1/4CTLA-4 Tg mice, aged 1/4CTLA-4 Tg mice had elevated frequencies of Foxp3 + regulatory T cells, but the regulatory T cells from these mice were not able to inhibit colitis development. Collectively, these data suggest that the function of the 1/4CTLA-4 isoform is distinct from that of CTLA-4 in that it enhances T cell activation and promotes autoimmunity rather than inhibiting immune responses. A member of the CD28 family of costimulatory receptors, CTLA-4 binds the same ligands as CD28, namely, B7.1 and B7.2. In contrast with CD28, CTLA-4 is a potent negative regulator of T cell activation, and deletion of Ctla4 has profound effects on peripheral tolerance (1–3). CTLA-4–deficient mice experience development of massive inflammatory infiltrates and tissue damage in multiple organs and exhibit early lethality. Deletion of both B7.1 and B7.2 rescues CTLA-4–deficient mice from lymphoproliferative disease, indicating that hyperactivation of T cells in CTLA-4 KO mice is the result of unchecked CD28/ B7 interactions in the absence of inhibitory signal via CTLA-4 (4). CTLA-4 expression is induced upon T cell activation and con-stitutively expressed on regulatory T (T-reg) cells (5, 6). CTLA-4 expression on natural T-reg cells is crucial for their suppressive function, because conditional deletion of CTLA-4 in Foxp3 + T-reg cells leads to a breakdown of peripheral tolerance and multiorgan tissue inflammation reminiscent of that in CTLA-4 KO (but slower in tempo) and scurfy mice carrying a Foxp3 gene mutation (7, 8). In addition, a recent study showed that silencing of the soluble form of CTLA-4 in T-reg cells impaired their suppressive …