Mice Gone Viral: Effect of Heterologous Infections On Alloreactivity of Mice.

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We have shown that renal allograft recipients who experience clinical costimulation blockade resistant rejection (CoBRR) have a higher percentage of CD57+PD1- CD4 T cells at transplantation compared to those without rejection. CD57 typically identifies senescent T cells, but can also be seen in other differentiated cells, e.g. follicular helper T cells. Mouse models typically have small numbers of differentiated cell populations such as these, largely due to limited environmental antigen exposure. Thus, to study the role of these cells in CoBRR in mice, we infected C57Bl6 mice with clinically relevant human virus homologues [Polyomavirus (PyV, murine BK virus), murine CMV, and HV68 (murine EBV)]. 5 groups of 10 mice were infected with mock, PyV, mCMV, HV68, or all 3. Blood was drawn at baseline, peak and memory time points and analyzed by flow cytometry, interrogating for markers of memory, differentiation, exhaustion and senescence. A significant increase in effector memory T cells was observed in both CD4 and CD8 compartments following every infection (p<0.05) that varied in size by virus type. Expression of PD1 was significantly up-regulated on CD8 T cells following every infection (p<0.05), and on CD4 T cells following infection with mCMV and HV68 (p<0.05). KLRG1, a murine marker of senescence and terminal differentiation, was significantly up-regulated on CD4 and CD8 T cells following infection with mCMV and HV68 (p<0.05). A significant increase in follicular helper T cells was also observed following every infection (p<0.05). Interestingly, H2-d reactive alloantibody was also induced at low levels by infection. These data demonstrate that a population of terminally differentiated cells can be generated by exposure to PyV, mCMV and HV68, and can stimulate alloantibody. We are currently performing heart transplants in infected mice to determine the effect of these cells on graft survival. These findings suggest that poly-viral exposure and the production of terminally differentiated T cells may drive heterologous alloreactivity. Cognizance of the differentiation status of the recipient immune repertoire may provide a means to stratify immunosuppression therapy.