NKG2D is an activating receptor for NK, NKT, CD8(+), and gammadelta(+) T cells, 
whose aberrant loss in cancer is a key mechanism of immune evasion. Soluble 
NKG2D ligands and growth factors, such as TGFbeta1 emanating from tumors, are 
mechanisms for down-regulating NKG2D expression. Cancers thereby impair the 
capacity of lymphocytes to recognize and destroy them. In this study, we show 
that exosomes derived from cancer cells express ligands for NKG2D and express 
TGFbeta1, and we investigate the impact of such exosomes on CD8(+) T and NK cell 
NKG2D expression and on NKG2D-dependent functions. Exosomes produced by various 
cancer cell lines in vitro, or isolated from pleural effusions of mesothelioma 
patients triggered down-regulation of surface NKG2D expression by NK cells and 
CD8(+) T cells. This decrease was rapid, sustained, and resulted from direct 
interactions between exosomes and NK cells or CD8(+) T cells. Other markers 
(CD4, CD8, CD56, CD16, CD94, or CD69) remained unchanged, indicating the 
selectivity and nonactivatory nature of the response. Exosomal NKG2D ligands 
were partially responsible for this effect, as down-modulation of NKG2D was 
slightly attenuated in the presence of MICA-specific Ab. In contrast, 
TGFbeta1-neutralizing Ab strongly abrogated NKG2D down-modulation, suggesting 
exosomally expressed TGFbeta as the principal mechanism. Lymphocyte effector 
function was impaired by pretreatment with tumor exosomes, as these cells 
exhibited poor NKG2D-dependent production of IFN-gamma and poor NKG2D-dependent 
killing function. This hyporesponsiveness was evident even in the presence of 
IL-15, a strong inducer of NKG2D. Our data show that NKG2D is a likely 
physiological target for exosome-mediated immune evasion in cancer.