Individual Effector/Regulator T Cell Ratios Impact Bone Regeneration

There is increasing evidence that T lymphocytes play a key role in controlling endogenous regeneration. Regeneration appears to be impaired in case of local accumulation of CD8+ effector T cells (T(EFF)), impairing endogenous regeneration by increasing a primary “useful” inflammation toward a damaging level. Thus, rescuing regeneration by regulating the heightened pro-inflammatory reaction employing regulatory CD4+ T (T(Reg)) cells could represent an immunomodulatory option to enhance healing. Hypothesis was that CD4+ T(Reg) might counteract undesired effects of CD8+ T(EFF). Using adoptive T(Reg) transfer, bone healing was consistently improved in mice possessing an inexperienced immune system with low amounts of CD8+ T(EFF). In contrast, mice with an experienced immune system (high amounts of CD8+ T(EFF)) showed heterogeneous bone repair with regeneration being dependent upon the individual T(EFF)/T(Reg) ratio. Thus, the healing outcome can only be improved by an adoptive T(Reg) therapy, if an unfavorable T(EFF)/T(Reg) ratio can be reshaped; if the individual CD8+ T(EFF) percentage, which is dependent on the individual immune experience can be changed toward a favorable ratio by the T(Reg) transfer. Remarkably, also in patients with impaired fracture healing the T(EFF)/T(Reg) ratio was higher compared to uneventful healers, validating our finding in the mouse osteotomy model. Our data demonstrate for the first time the key-role of a balanced T(EFF)/T(Reg) response following injury needed to reach successful regeneration using bone as a model system. Considering this strategy, novel opportunities for immunotherapy in patients, which are at risk for impaired healing by targeting T(EFF) cells and supporting T(Reg) cells to enhance healing are possible.