Donor-specific memory T cells pose an unaddressed challenge to transplantation, as higher pre-transplant frequencies of donor-specific memory T cells correlate with worse long-term graft function and acute rejection rates.  These donor-specific memory T cells may be induced by either prior exposure to donor MHC (via failed prior transplant, blood transfusion or pregnancy) or by heterologous immunity, in which memory T cells generated in response to pathogens prove cross-reactive to donor antigens.  A recent study highlighted the importance of heterologous immunity in generating alloreactive memory T cells in human patients, revealing that 45% of memory T cells generated after exposure to common viruses possessed alloreactive potential.

To study mechanisms of costimulatory blockade-resistant rejection, we developed an experimental transplant system that models donor-specific recall CD8⁺ T cell responses.  We sought to identify critical molecules utilized by pathogen-elicited memory T cells to mediate transplant rejection in the presence of costimulatory blockade. Results indicated that the resistance of memory T cells to costimulatory blockade was abrogated when costimulatory blockade was coupled with either anti-VLA-4 or anti-LFA-1.  In the presence of costimulatory blockade, these integrin antagonists equivalently prolonged graft survival, but did so through distinct mechanisms. Specifically, anti-LFA-1 predominately attenuated recall effector functions, while anti-VLA-4 restricted secondary effector/ memory T cell trafficking to the graft.  As antagonists against these integrins are already clinically approved for use in autoimmunity, these findings have significant translational potential for future clinical transplant trials.

Results from the above experiments suggested that integrin antagonists could couple with costimulatory blockade in inhibiting donor-reactive memory T cell responses.  However, it is well appreciated that memory T cell populations exhibit heterogeneity both in terms of phenotype and functionality, depending on the conditions under which they were primed.  In order to determine how stimulation history impacted the relative dependence of donor-reactive memory T cells on combined costimulatory/integrin blockade, we compared the efficacy of this regimen in mice that been infected with an acute, recurrent, or latent viral infection.  Results indicated a striking dichotomy in the efficacy of costimualtory/integrin pathway blockade based on the stimulation history of the recipient: while mice that had received a single acute infection enjoyed long-term graft survival, recipients of latent or persistent viral infections rapidly and consistently rejected their grafts.  Delineating the mechanisms by which donor-reactive memory T cells generated through latent or persistent infections subvert the requirement for these pathways during recall responses is the an important are of future research.