AUTHOR=Schlundt Claudia , Reinke Simon , Geissler Sven , Bucher Christian H. , Giannini Carolin , Märdian Sven , Dahne Michael , Kleber Christian , Samans Björn , Baron Udo , Duda Georg N. , Volk Hans-Dieter , Schmidt-Bleek Katharina 

TITLE=Individual Effector/Regulator T Cell Ratios Impact Bone Regeneration

JOURNAL=Frontiers in Immunology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.01954

DOI=10.3389/fimmu.2019.01954

ISSN=1664-3224

ABSTRACT=<p>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<sub>EFF</sub>), 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<sub>Reg</sub>) cells could represent an immunomodulatory option to enhance healing. Hypothesis was that CD4+ T<sub>Reg</sub> might counteract undesired effects of CD8+ T<sub>EFF</sub>. Using adoptive T<sub>Reg</sub> transfer, bone healing was consistently improved in mice possessing an inexperienced immune system with low amounts of CD8+ T<sub>EFF</sub>. In contrast, mice with an experienced immune system (high amounts of CD8+ T<sub>EFF</sub>) showed heterogeneous bone repair with regeneration being dependent upon the individual T<sub>EFF</sub>/T<sub>Reg</sub> ratio. Thus, the healing outcome can only be improved by an adoptive T<sub>Reg</sub> therapy, if an unfavorable T<sub>EFF</sub>/T<sub>Reg</sub> ratio can be reshaped; if the individual CD8+ T<sub>EFF</sub> percentage, which is dependent on the individual immune experience can be changed toward a favorable ratio by the T<sub>Reg</sub> transfer. Remarkably, also in patients with impaired fracture healing the T<sub>EFF</sub>/T<sub>Reg</sub> 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<sub>EFF</sub>/T<sub>Reg</sub> 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<sub>EFF</sub> cells and supporting T<sub>Reg</sub> cells to enhance healing are possible.</p>