CTLA‐4 expression regulation and its functions in systemic lupus erythematosus (SLE)

Abstract

Cytotoxic T lymphocyte Antigen 4 (CTLA‐4) is an important inhibitory signaling molecule of T cell. There are 4 splice variants in human and mice suggesting its functional importance. We characterized the CTLA‐4 splice variant expression regulation and their biological significance in both human and mouse SLE T cells. The residual expression of the full length (FL) CTLA‐4 mRNA was increased in resting T cells of SLE patients (p < 0.01) and lupus‐prone mouse strains MRL/lpr and C57B6/lpr. However, following activation, the peak expression of FL CTLA‐4 mRNA was lower than control T cells. Additionally, mRNA degradation increased by 2.7 fold in human SLE T cells compare to healthy T cells. Furthermore, we found a 2.4 fold increase in T cells of MRL/lpr compared to control T cells of MPJ mice. The short splice variant of CTLA‐4 (encoding exons 1 and 4) showed exactly opposite kinetics than the FL CTLA‐4. It was decreased in resting T cell and displayed decreased mRNA degradation. Protein expression pattern was the same as mRNA expression for both splice variants. These findings suggest that CTLA‐4 short splice variant may act differently to the FL CTLA‐4 in SLE T cell activation. This inverse relationship between short splice variant and FL CTLA‐4 may have a profound effect on effector CD4+ T cell activation and signaling.