A chemokine-to-cytokine-to-chemokine cascade critical in antiviral defense

Macrophage inflammatory protein 1 alpha (MIP-1 alpha) promotes natural kill er (NK) cell inflammation in livers during murine cytomegalovirus (MCMV) in fections, and NK cell-produced interferon gamma (IFN-gamma) contributes to defense against MCMV infections. A specific role for local NK cell IFN-gamm a production, however, has not been established. The importance of MIP-1 al pha and NK cell-produced IFN-gamma in shaping endogenous immune responses a nd defense in different compartments was examined. MIP-1 alpha deficiency p rofoundly decreased resistance to MCMV and was associated with dramatically reduced NK cell accumulation and IFN-gamma production in liver. MIP-1 alph a-independent IFN-gamma responses were observed in serum and spleen, and in fection-induced elevations in blood NK cell populations occurred in absence of the factor, but peak Liver expression of another chemokine, the monokin e induced by IFN-gamma (Mig), depended upon presence of MIP-1 alpha, NK cel ls, and IFN-gamma. The Mig response was also important for viral resistance . Thus, serum cytokine responses are insufficient; MIP-la is critical for N K cell migration and IFN-gamma delivery to mediate protection; and Mig indu ction in tissues is a downstream protective response resulting from the pro cess. These results define a critical chemokine-to-cytokine-to-chemokine ca scade required for defense during a viral infection establishing itself in tissues.