Among the many human mutations that lead to a pathological condition, few have a spontaneous orthologous equivalent in the mouse and vice versa. In this regard, the spf-J mouse is a unique tool for studying mild OTC deficiency. Several factors are required to trigger an autoimmune organ-specific disease. Genetic and environmental components will collaborate to cause a breakdown of the peripheral immune tolerance and activation of resident cells of affected tissues. Autoimmune uveitis illustrates these autoimmunity paradigms. Genetic susceptibility of individuals with AIU has been widely studied and the association of several polymorphisms at Perifosine different loci of the HLA system is well known. Similarly, different groups have demonstrated the presence of autoreactive T cells and the role of cytokines released by these cells in the activation of resident cells of the eye during development of AIU. Several data also attest the importance of the role of danger signals during these two key phases of pathological activation. If a central place was given to exogenous danger signals, in particular microbial, the importance of endogenous danger signals began to emerge. In this context, nucleotides are an important family of potential endogenous danger signals. In fact, normally, they are present almost exclusively within the cells. However, during cellular destruction or stress, like inflammation, nucleotides can be released in various amounts in the extracellular space and activate nucleotide receptors belonging to the P2X and P2Y families. In many cases, the activation of P2 receptors results in an increase of the inflammatory process. In agreement with the danger signal theory, we have shown that different nucleotides, ATPγS, UTP and UDP, are involved in the activation of retinal pigment epithelium and increase the basal as well as the TNFα-induced release of IL-8. Similarly, several works have demonstrated that nucleotides also profoundly influence antigen presentation and lymphocyte activation. Accordingly, Granstein et al have shown, in vivo, that extracellular nucleotides strongly increase lymphocyte activation after systemic immunization. In this work, we have thus hypothesized that nucleotides can act as danger signals during AIU and interfere with both the activation of autoreactive lymphocytes and the stimulation of blood retinal barrier cells. The development of autoimmune uveitis requires both the activation of retinal specific autoreactive lymphocyte clones, their migration to the eye and the breakdown of the blood retinal barrier. In this work, we found that P2Y2 deficiency attenuates EAU development and strongly affects the activation of IRBP-specific autoreactive lymphocytes after systemic immunization. Our results are in accordance with the danger model, which makes a link between autoreactive lymphocyte activation, immune cell migration and the release of endogenous danger signals such as extracellular nucleotides. Among them, extracellular ATP was recognized as an important modulator of immune responses through its binding to plasma membrane P2 purinergic receptors.