Thy1+ NK [corrected] cells from vaccinia virus-primed mice confer protection against vaccinia virus challenge in the absence of adaptive lymphocytes

While immunological memory has long been considered the province of T- and B- lymphocytes, it has recently been reported that innate cell populations are capable of mediating memory responses. We now show that an innate memory immune response is generated in mice following infection with vaccinia virus, a poxvirus for which no cognate germline-encoded receptor has been identified. This immune response results in viral clearance in the absence of classical adaptive T and B lymphocyte populations, and is mediated by a Thy1+ subset of natural killer (NK) cells. We demonstrate that immune protection against infection from a lethal dose of virus can be adoptively transferred with memory hepatic Thy1+ NK cells that were primed with live virus. Our results also indicate that, like classical immunological memory, stronger innate memory responses form in response to priming with live virus than a highly attenuated vector. These results demonstrate that a defined innate memory cell population alone can provide host protection against a lethal systemic infection through viral clearance.
Author Summary Immunological memory is a hallmark of adaptive immunity and provides the basis for our ability to become ‘immune’ to pathogens to which we have previously been exposed, and provides the basis for vaccination. For decades, the paradigm held that only the classical adaptive lymphocytes were capable of forming and maintaining protective immunological memory. Recently, several papers have shown the capacity of an innate cell population, a subset of natural killer (NK) cells, to exhibit certain aspects of immunological memory. Here we show that innate memory forms in response to infection with vaccinia virus and resides in a discrete subset of NK cells. We further demonstrate that this innate memory provides significant host protection against a subsequent systemic infection with a lethal dose of vaccinia virus, in some cases resulting in the complete clearance of detectable virus. We also demonstrate that priming with live, replicating virus stimulates innate memory more robustly than a highly attenuated vector. These findings shed new light on this emergent area of immunology, and hold significant implications for harnessing innate memory as part of creating novel vaccination strategies.