There is evidence demonstrating that CD28 can translocate to lipid rafts upon cross-linking and that this correlates with its co-stimulation of IL-2 production. OCILRP2 may play a role similar to that of CD28 by facilitating TCR-mediated raft microdomain formation. T cell receptor signal transduction is initiated by the assembly and aggregation of signaling complexes including the adaptor molecule LAT, the Src homology 2 domain-containing leukocyte protein of 76 kDa, Lck, and Fyn. OCILRP2 may be recruited to lipid rafts and facilitate Lck tyrosine phosphorylation. Because human DAP12 reportedly binds the SH2 domains of Syk and Zap-70, the ligation of OCILRP2 may lead to the activation of Syk and Zap70. MAPKs are regarded as key switches of cellular activation and proliferation. Within the context of co-stimulatory OCILRP2 signaling, an increase in Jnk or Erk phosphorylation was observed. The phosphorylation of Raf was inhibited by si-OCILRP2, suggesting that Raf might be essential for the regulation of CD3/CD28 antibody-induced IL-2 expression. The pathway revealed by our findings provides a molecular basis for the defective TCR-mediated activation of OCILRP2- silenced mouse T lymphocytes. Therefore, selective pharmacological strategies designed to modulate the recruitment of OCILRP2 to the cell membrane may prove therapeutically useful for modulating T cell co-stimulatory signals in immunological diseases. Uromodulin-associated kidney disease is a rare dominant hereditary renal disease caused by amino acid-changing mutations in the uromodulin gene. Patients with UAKD exhibit impaired urinary concentration ability, in most cases hyperuricemia, morphological kidney alterations like progressive ALK5 Inhibitor II tubulointerstitial damage and sometimes renal cysts and constantly develop disease progression up to renal failure. Dysfunction of thick ascending limb of Henle’s loop cells due to mutant UMOD maturation retardation and retention in the hyperplastic endoplasmic reticulum represents the key pathogenic mechanism of UAKD. Uromodulin is selectively expressed in cells of the TALH and of the early distal convoluted tubules. After UMOD synthesis in the ER and extensive glycosylation, the mature protein is translocated to the luminal cell membrane and released into urine by proteolytic cleavage. UMOD represents the most abundant protein in human urine. Although this glycoprotein was already discovered in the early fifties by Tamm and Horsfall, the biological function of UMOD is still obscure. Studies on Umod knockout mice revealed a protective role of UMOD against ascending urinary tract infections e.g. of type 1-fimbriated E. coli, and a protective role against calcium oxalate crystal formation in the kidney. Further, UMOD might have a role in innate immune system and might act as an endogenous danger signal after tubular damage that leads to exposition of UMOD protein to mononuclear cells like dendritic cells in the kidney interstitium. In various genome-wide association studies, common allelic UMOD promoter variants were identified to be associated with increased risk for complex trait diseases like chronic kidney disease, hypertension and kidney stones.