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-R(eg) might counteract undesired effects of CD8+ T-EFF. Using adoptive T(Re)g 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-R(eg) 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-R(eg) 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.