Viral infections have been associated with the rejection of transplanted allografts in humans and mice, and the induction of tolerance to allogeneic tissues in mice is abrogated by an ongoing viral infection and inhibited in virus-immune mice. members of the herpesvirus group in humans (1C4). Virus-induced rejection of transplanted tissues is also evident in mice, even occurring under conditions of tolerization to alloantigens by a costimulation blockade that substantially reduces the number of alloreactive T cells (4C6). The association of viral infections with allograft rejection might be predicted, due to the fact that viral infections often stimulate the outgrowth of alloreactive T cells that cross-react with virus-derived antigens in the absence of alloantigens (7C12). For example, acute LCMV infection of C57BL/6 (B6) (or CBA/J, = 0.013). These data indicate that effector virus-specific CD8 T cells are able to reject skin allografts. Figure 5 LCMV-specific CD8 T cells mediate rejection of skin allografts DISCUSSION Viral infections are a serious complication for transplant recipients and are often associated with rejection of engrafted tissues. Historically, herpes viruses such as CMV, EBV and HSV, were the primary concern for transplant recipients, but other viruses, including influenza virus and polyoma viruses (BK and JC virus) are also problematic KB130015 manufacture (2, 36C39). In this report, we show that LCMV-specific memory CD8 T cells proliferate in response to alloantigens both in vitro and in vivo. This represents, to our knowledge, the first demonstration that virus-specific memory CD8 T cells are recruited into the immune response against tissue allografts in vivo. The alloantigen-induced division of LCMV-specific memory CD8 T cells involved multiple epitope-specific populations, which varied between individual mice. The variation between individuals was attributed to the unique private specificity of the memory T cell pool for each mouse. These results demonstrate that virus-specific KB130015 manufacture CD8 T cells generated by past viral infections will respond against foreign tissue grafts and that the epitope-specificity of this cross-reactive response will be dictated by an individuals unique TCR repertoire. Our study makes the observation that virus-reactive CD8 T cells proliferate in response to alloantigens and that the epitope-specificity of the proliferating cells is variable between individual mice, with distinct patterns of epitope-specific populations responding. This diversity in the activation of cross-reactive memory CD8 T cells was also observed in models of sequential viral infections with LCMV and VV and with LCMV and PV (33, 34). Our results reinforce the concept that the virus-specific CD8 T cells from individual mice have a unique epitope-specific TCR-repertoire and that this private specificity will impact directly on the induction of an allo-cross-reactive T cell response (33, 34). Memory alloreactive T cells are a serious concern for transplant patients, as the pre-transplant frequency of donor-reactive memory T cells correlates with the likelihood of an acute rejection episode (22). Memory alloreactive CD8 T cells respond rapidly to transplanted tissues in mice and produce inflammatory cytokines, which stimulate the allograft to secrete chemokines that enhance the recruitment of innate immune cells, such as polymorphonuclear leukocytes, to the engraftment site (40). The survival of virus-induced KB130015 manufacture cross-reactive T cells into memory may account for the detection of alloreactive memory CD8 T cells in humans never been exposed to alloantigens (13, 22). Previous studies have suggested that cross-reactive virus-specific CD8 T cells are an important consideration for transplantation patients. For example, human CD8 T cells specific for an EBV-epitope (FLRGRAYGL) presented by HLA-B8 recognize HLA molecules B14, B44 and B35 as alloantigens (12, 17), and HLA-B44-positive renal transplants show decreased survival in HLA-B8 positive recipients (7). Our findings presented in Figure 5 indicate that a population of effector CD8 T cells specific for an individual virus-derived epitope can mediate the rejection of a skin allograft. Although we used mice acutely infected with LCMV for this experiment in order to obtain sufficient numbers of T cells, we predict that MMP11 virus-specific memory CD8 T cells will also mediate rejection of transplanted tissues and that this population will differ between LCMV-immune hosts due to the variability in the allo-cross-reactive repertoire. In these experiments it was not meaningful to use a control non-tetramer-specific population, because cross-reactive alloreactive T cells are found among T cells with other viral epitope specificities (Figures 2, ?,33 and ?and4)4).