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Human cytomegalovirus is a paradigm for studies of viral strategies of immune evasion. In particular, the virus has developed multiple mechanisms for evasion of immune surveillance by lymphocytes expressing the activating receptor NKG2D. The human genome encodes several ligands able to bind NKG2D and in this article we review and discuss what is known about the various viral proteins and micro RNAs that act to minimise the recognition of the infected cell by modulation of the expression and trafficking of the different NKG2D ligand molecules.

ABSTRACTImmunotherapy, via intra-vesical instillations of BCG, is the therapy of choice for patients with high-risk non-muscle invasive bladder cancer. The subsequent recruitment of lymphocytes and myeloid cells, as well as the release of cytokines and chemokines, is believed to induce a local immune response that eliminates these tumors, but the detailed mechanisms of action of this therapy are not well understood. Here, we have studied the phenotype and function of the responding lymphocyte populations as well as the spectrum of cytokines and chemokines produced in an in vitromodel of human peripheral blood mononuclear cells (PBMCs) co-cultured with BCG. Natural killer (NK) cell activation was a prominent feature of this immune response and we have studied the expansion of this lymphocyte population in detail. We show that, after BCG stimulation, CD56dimNK cells proliferate, upregulate CD56, but maintain the expression of CD16 and the ability to mediate ADCC. CD56brightNK cells also contribute to this expansion by increasing CD16 and KIR expression. These unconventional CD56brightcells efficiently degranulated against bladder cancer cells and the expansion of this population required the release of soluble factors by other immune cells in the context of BCG. Consistent with these in vitrodata, a small, but significant increase in the intensity of CD16 expression was noted in peripheral blood CD56brightcells from bladder cancer patients undergoing BCG therapy, that was not observed in patients treated with mitomycin-C instillations. These observations suggest that activation of NK cells may be an important component of the anti-tumoral immune response triggered by BCG therapy in bladder cancer.