Schoenberger: I'd like to think that this is because it provides new and perhaps unexpected answers to a question that has interested cellular immunologists for more than 25 years. Understanding how the "help" provided by CD4 T lymphocytes influences the response of CD8 T lymphocytes has been the focus of numerous studies which had produced an accepted model in which two types of CD8 T cell responses (CD4-dependent and CD4-independent) were thought to exist. Our work provided a unifying hypothesis for these observations by showing that there are CD4-independent and CD4-dependent stages of a CD8 T cell response. Our work also revealed a direct link between CD4 T cell help and the establishment of immune memory by CD8 T cells. I suspect that the impact of our findings was enhanced by a pair of studies published several months afterwards that confirmed our results.

Schoenberger: Yes, in addition to shedding light on a fundamental aspect of immune regulation which may have parallels in other areas of cellular biology, our findings provide new information that is relevant for vaccination strategies aimed at eliciting effective CD8 T cell responses, as well as for understanding how CD8 T cell responses may still be possible in immunocompromised individuals who may lack an intact CD4 T cell compartment.

Schoenberger: Our paper showed that the primary expansion of CD8 T cells in response to immunization can proceed in the absence of CD4 T helper cells. The capacity for these cells to undergo a second round of clonal expansion requires that they were primed in the presence of CD4 T cells. Our work therefore showed that the capacity to undergo secondary expansion, a hallmark of T cell memory is "programmed" into the CD8 T cells during their primary activation in the presence of CD4 T help. This was found to be true for what had been referred to in the literature as "CD4-dependent" and "CD4-independent" CD8 T cell responses.