title: Terminally differentiated CD8⁺ T cells negatively affect bone regeneration in humans.
abstract: There is growing evidence that adaptive immunity contributes to endogenous regeneration processes: For example, endogenous bone fracture repair is modulated by T cells even in the absence of infection. Because delayed or incomplete fracture healing is associated with poor long-term outcomes and high socioeconomic costs, we investigated the relationship between an individual's immune reactivity and healing outcome. Our study revealed that delayed fracture healing significantly correlated with enhanced levels of terminally differentiated CD8(+) effector memory T (TEMRA) cells (CD3(+)CD8(+)CD11a(++)CD28(-)CD57(+) T cells) in peripheral blood. This difference was long lasting, reflecting rather the individual's immune profile in response to lifelong antigen exposure than a post-fracture reaction. Moreover, CD8(+) TEMRA cells were enriched in fracture hematoma; these cells were the major producers of interferon-γ/tumor necrosis factor-α, which inhibit osteogenic differentiation and survival of human mesenchymal stromal cells. Accordingly, depletion of CD8(+) T cells in a mouse osteotomy model resulted in enhanced endogenous fracture regeneration, whereas a transfer of CD8(+) T cells impaired the healing process. Our data demonstrate the high impact of the individual adaptive immune profile on endogenous bone regeneration. Quantification of CD8(+) TEMRA cells represents a potential marker for the prognosis of the healing outcome and opens new opportunities for early and targeted intervention strategies.
authors.affiliation: Berlin-Brandenburg Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Berlin 13353, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Reinke
authors.forename: Sven
authors.initials: S
authors.lastname: Geissler
authors.forename: William R
authors.initials: WR
authors.lastname: Taylor
authors.forename: Katharina
authors.initials: K
authors.lastname: Schmidt-Bleek
authors.forename: Kerstin
authors.initials: K
authors.lastname: Juelke
authors.forename: Verena
authors.initials: V
authors.lastname: Schwachmeyer
authors.forename: Michael
authors.initials: M
authors.lastname: Dahne
authors.forename: Tony
authors.initials: T
authors.lastname: Hartwig
authors.forename: Levent
authors.initials: L
authors.lastname: Akyüz
authors.forename: Christian
authors.initials: C
authors.lastname: Meisel
authors.forename: Nadine
authors.initials: N
authors.lastname: Unterwalder
authors.forename: Navrag B
authors.initials: NB
authors.lastname: Singh
authors.forename: Petra
authors.initials: P
authors.lastname: Reinke
authors.forename: Norbert P
authors.initials: NP
authors.lastname: Haas
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Volk
authors.forename: Georg N
authors.initials: GN
authors.lastname: Duda
mesh_terms: D000328:Adult; D001861:Bone Regeneration / Q000276:immunology* / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D005260:Female; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D008875:Middle Aged; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D055815:Young Adult
chemical_list: D014409:Tumor Necrosis Factor-alpha