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.

Research in Fracture Healing and Its Clinical Applications in the Veterinary Practice

“…No cartilage remains; 28 days: remodeling phase. Histological samples stained with Movat Pentachrome: bone = yellow; bone marrow =purple; cartilage = blue-green, muscle = orange; connective tissue = light blue [2,4,6,15,[34][35][36][37][38][39][40][41][42][43]. Periost has been carefully elevated from the bone and was stained with hematoxylin eosin.…”

Interactions Between Multipotential Stromal Cells (MSCs) and Immune Cells During Bone Healing

“…Both TNF-and IFN-inhibited MSC osteogenic ability in dose-dependent manner in vitro (180). Interestingly, an in vitro exposure to IFN-augmented TNF--mediated apoptosis of BM MSCs and suppressed their osteogenic differentiation (182,191).…”

“…Moreover, a depletion of these CD8 + T lymphocytes leads to an improvement of bone repair in an osteotomy mouse model (180). In another study, activated Th1 cells or cytotoxic T lymphocytes were found to block osteogenic differentiation of MSCs via the effect of IFN-(181).…”

Immune system and regulation of regeneration

“…Показано, что ýта популяция лимфоцитов продуцирует IFNγ (интерферон гамма) и TNFα, которые ингибируют приживаемость и остеогенную дифференцировку мезенхимальных стромальных клеток. По данным авторов, истощение популяции Т-лимфоцитов CD8(+) у мышей ускоряет заживление у живот-ных костных переломов, в то время как транс-плантация ýтих клеток тормозит процесс [26].…”

“…Показано, что ýта популяция лимфоцитов продуцирует IFNγ (интерферон гамма) и TNFα, которые ингибируют приживаемость и остеогенную дифференцировку мезенхимальных стромальных клеток. По данным авторов, истощение популяции Т-лимфоцитов CD8(+) у мышей ускоряет заживление у живот-ных костных переломов, в то время как транс-плантация ýтих клеток тормозит процесс [26].На примере регенерирующей печени показано, что передача спленоцитами и тимоцитами мор-фогенетического сигнала и его характер обуслов-лены различными клетками иммунной системы: внутриклеточный тип регенерации -преимуще-ственно независимыми от макрофагов Т-лимфо-цитами, а клеточный -макрофагами и зависимы-ми от них лимфоцитами. При ýтом существенную роль играет функциональное состояние лимфо-идных клеток регенерирующей ткани.…”