Virtual memory cells make a major contribution to the response of aged influenza-naive mice to influenza virus infection

Abstract

Abstract The ability to mount adaptive immune responses is impaired with age. One important contributing factor is the dramatic decline in repertoire and number of naïve T cells, raising the possibility that the response to new infections relies largely on cross-reactive memory T cells. We have analyzed the CD8 T cell response to influenza virus in influenza-naïve aged mice and confirmed that memory phenotype cells do make a major contribution to the response to new infections. There are two possible origins of the responding memory T cells. The response may be mediated by fortuitously cross reactive memory cells that were generated by earlier heterologous infections, which can be defined as “true memory” (TM). This possibility is supported by the observations that T cell recognition is highly degenerate and many unexpected cross-reactivities have been defined. Alternatively, the response may be mediated by antigen-specific memory cells that have been generated in the absence of antigen exposure, termed “virtual memory” (VM) cells. This possibility is supported by the observation that the ratio of VM:TM increases dramatically with age. To determine whether TM or VM respond to influenza in aged mice we used dual adoptive transfer with VM and TM cells. The data show that the response to influenza virus is dominated by memory CD8 T cells with a VM phenotype. The ability of these cells to afford protective immunity and develop into long-lived memory cells is under investigation and has implications for our understanding of immune function in the aged.