Donor Allospecific CD44^high Central Memory T Cells Have Decreased Ability to Mediate Graft-vs.-Host Disease

Data from both animal models and humans have demonstrated that effector memory T cells (T_EM) and central memory T cells (T_CM) from unprimed donors have decreased ability to induce graft-vs-host disease (GVHD). Allospecific T_EM from primed donors do not mediate GVHD. However, the potential of alloreactive T_CM to induce GVHD is not clear. In this study, we sought to answer this question using a novel GVHD model induced by T cell receptor (TCR) transgenic OT-II T cells. Separated from OT-II mice immunized with OVA protein 8 weeks earlier, the allospecific CD44^high T_CM were able to mediate skin graft rejection after transfer to naive mice, yet had dramatically decreased ability to induce GVHD. We also found that these allospecific CD44^high T_CM persisted in GVHD target organs for more than 30 days post-transplantation, while the expansion of these cells was dramatically decreased during GVHD, suggesting an anergic or exhausted state. These observations provide insights into how allospecific CD4⁺ T_CM respond to alloantigen during GVHD and underscore the fundamental difference of alloresponses mediated by allospecific T_CM in graft rejection and GVHD settings.