In the ULBP family of human ligands (19,147). Splice variant transcripts of ULBP5 (RAET1G) encoded by the RAET1G2 gene, was detected within a T cell Caspase-10 Proteins Species leukemia line, while in this study the presence of soluble protein inside the cell supernatant was not analyzed (19). Related to ULBP5, ULBP4 (RAET1E) can also be alternatively spliced to generate the soluble RAET1E2 kind (147). These research highlight that as well as proteolytic cleavage at the protein level, option splicing at the RNA level may well play a vital function in NKG2D immune evasion. Mouse models to know the consequences of soluble ligands Till not too long ago, most studies investigating the part of soluble NKG2D in tumorigenesis have already been solely correlative. Defining the part of soluble ligands in human cancer progression is complicated by the fact that tumors secrete various things that may well influence NKG2D function autonomously, like TGF- (14850). The initial study suggesting an immunomodulatory role of soluble MICA (sMICA) in cancer individuals showed a correlation amongst the presence of soluble MICA in sera of patients with MICA+ epithelial tumors as well as the level of NKG2D down-regulation on tumor-infiltrating and peripheral blood CD8+ T cells (116). Furthermore, incubation of CD8+ T cells with sera from sufferers with MICA+ tumors decreased the amount of NKG2D on CD8+ T cells. Nevertheless, these sera may well have contained other NKG2D-modulating things including TGF-. Of note nonetheless, incubation of human lymphocytes in higher amounts of recombinant sMICA (100 ng/mL) did lead to a decrease in surface NKG2D expression. Utilizing a mouse model in which human MICA was expressed under the H-2Kb promoter, Wiemann et al. also detected secreted MICA in the sera with the mice; having said that, sMICA could not downregulate NKG2D. Incubation of wildtype splenocytes with MICA-transgenic (Tg) splenocytes modulated surface NKG2D levels on wildtype splenocytes, but soluble MICA (sMICA) from MICA-Tg mice sera didn’t. This distinction could be due to differential binding affinities of MICA to mouse and human NKG2D. In extra studies, neither sULBP2 nor sMICA/B could downregulate NKG2D levels on the human NK cell lines NKL (117,133). Within this situation, NKG2D affinity to human NKG2D ligands is just not an issue. Altogether, these findings raise the important question on the physiological role of soluble NKG2D ligands during tumorigenesis. Is tumor shedding of NKG2D ligands an efficient mechanism by which tumors evade NK cell immunosurveillance A recent study investigated this exact question by designing a set of constructs encoding unique variants of MICB. MICB was expressed either as a full-length protein (MIC), a CPVL Proteins Biological Activity shedding-resistant protein (MICA-A2), or possibly a soluble protein (rsMIC). MICAA2 contained an amino acid substitution in the 3 domain of MICB producing it resistant to protease action. sMIC was generated by deleting the transmembrane and cytoplasmic regions of MICB. The authors transduced a prostate tumor model TRAMP-C2 (TC2) cell line with the diverse constructs and showed that shedding-resistant MIC-A2 prevented TC2 tumorNIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptImmunol Rev. Author manuscript; accessible in PMC 2011 May well 1.Champsaur and LanierPageformation, whereas sMIC allowed for more quickly TC2 tumor growth. These findings support the hypothesis that soluble NKG2D ligands secreted by tumor cells can enhance tumor growth in vivo. Following these findings, the authors hypoth.