Premature Senescence of T-cells Favors Bone Loss During Osteolytic Diseases. A New Concern in the Osteoimmunology Arena.

Alfredo Sierra-Cristancho,Angélica M Cárdenas,Carolina Rojas,Emilio A Cafferata,Luis González-Osuna,Rolando Vernal,Samanta Melgar-Rodríguez

doi:10.14336/ad.2021.0110

Abstract

Cellular senescence is a biological process triggered in response to time-accumulated DNA damage, which prioritizes cell survival over cell function. Particularly, senescent T lymphocytes can be generated prematurely during chronic inflammatory diseases regardless of chronological aging. These senescent T lymphocytes are characterized by the loss of CD28 expression, a co-stimulatory receptor that mediates antigen presentation and effective T-cell activation. An increased number of premature senescent CD4+CD28- T lymphocytes has been frequently observed in osteolytic diseases, including rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, osteopenia, osteoporosis, and osteomyelitis. Indeed, CD4+CD28- T lymphocytes produce higher levels of osteoclastogenic molecular mediators directly related to pathologic bone loss, such as tumor necrosis factor (TNF)-α, interleukin (IL)-17A, and receptor-activator of nuclear factor κB ligand (RANKL), as compared with regular CD4+CD28+ T lymphocytes. In addition, premature senescent CD8+CD28- T lymphocytes have been negatively associated with bone healing and regeneration by inhibiting osteoblast differentiation and mesenchymal stromal cell survival. Therefore, accumulated evidence supports the role of senescent T lymphocytes in osteoimmunology. Moreover, premature senescence of T-cells seems to be associated with the functional imbalance between the osteolytic T-helper type-17 (Th17) and bone protective T regulatory (Treg) lymphocytes, as well as the phenotypic instability of Treg lymphocytes responsible for its trans-differentiation into RANKL-producing exFoxp3Th17 cells, a key cellular phenomenon directly related to bone loss. Herein, we present a framework for the understanding of the pathogenic characteristics of T lymphocytes with a premature senescent phenotype; and particularly, we revise and discuss their role in the osteoimmunology of osteolytic diseases.

Highlights

Cellular senescence is a biological process triggered in response to time-accumulated DNA damage, which prioritizes cell survival over cell function
Even though multiple pathways can lead to cellular senescence and result in diverse senescent phenotypes, these pathways seem to converge into a common cell phenotype transversal to the different types of senescent cells (Fig. 1) [2, 3]
In the context of osteoimmunology, the activity of T lymphocytes with senescent phenotype contributes to a novel understanding of the cross-communication between the immune response and bone metabolism

Summary

Introduction

Cellular senescence is a biological process triggered in response to time-accumulated DNA damage, which prioritizes cell survival over cell function. This inflammatory milieu further favors the production of pro-inflammatory cytokines, including IFN-γ, TNF-α, and IL-1β, which can induce the expression of RANKL in osteoblasts and fibroblasts with osteoclastogenic capacity, generating a complex network of RANKL-producing cells that contribute even more to pathologic bone loss [46].

Results

Conclusion