UC Berkeley

Natural killer (NK) cells are lymphocytes that play a major role in the elimination of virally-infected cells and tumor cells. NK cells recognize and target abnormal cells through activation of stimulatory receptors such as NKG2D. NKG2D ligands are self-proteins, which are absent or expressed at low levels on healthy cells but are induced upon cellular stress, transformation, or viral infection. The exact molecular mechanisms driving expression of these ligands remain poorly understood.

Using mouse cytomegalovirus (MCMV) as a model, the present dissertation describes three distinct factors that contribute to the induction of the RAE-1 family of NKG2D ligands during MCMV infection. First, we show that activation of the phosphatidylinositol-3-kinase (PI3K) pathway, which is often dysregulated during infection and tumorigenesis, is required for RAE-1 expression in MCMV-infected cells as well as in transformed cell lines. Second, genetic manipulation of the MCMV genome has revealed a novel viral protein encoded by the m18 gene that is both necessary and sufficient to induce RAE-1 expression. Finally, studies using mouse strains that are deficient in various innate signaling molecules demonstrate that innate signaling through the MyD88 adaptor protein and the IRF3 transcription factor are involved in RAE-1 induction.

Collectively, we have shown that RAE-1 expression during MCMV infection involves a combination of signals to ensure that its expression is limited to truly diseased cells.