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

Senescent CD4+CD28− T Lymphocytes as a Potential Driver of Th17/Treg Imbalance and Alveolar Bone Resorption during Periodontitis

“…However, some phenotypic characteristics appear to be conserved independently of these factors and are frequently used to identify senescent cells ( Figure 2 ). In this context, the main hallmark of cellular senescence is cell cycle arrest, which occurs immediately after damage to the genetic material by the activation of the DNA damage response (DDR), through the recruitment and activation of ataxia-telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related protein (ATR) [ 7 , 12 ]. These changes lead to the phosphorylation of H2A histone family member X (γ-H2AX) and the upregulation of cell cycle inhibitors such as p21 and p16 ink4a in order to prevent replication of defective cells by blocking their proliferative capacity [ 7 , 12 ].…”

“…Indeed, senescent dendritic cells induced by P. gingivalis infection are capable of triggering paracrine senescence in non-senescent dendritic cells after internalization of the SASP-loaded exosomes produced by them, without the need for cell-to-cell contact [ 21 ]. Thus, a vicious circle of inflammaging is established, in which SASP components induce senescence, and senescence further contributes to the maintenance of inflammation through SASP [ 7 ].…”

“…However, it is important to note that there is currently no single reliable marker to identify senescent cells. Therefore, combinations of some hallmarks of the cellular senescence process are used, such as the loss of CD28 expression in the T cell compartment, which has been proposed as a marker of immunosenescence that allows the identification of senescent CD4 + T lymphocytes [ 7 ].…”

“…In this sense, recent reports suggest that pathologic changes in the periodontitis-affected tissues could create a favorable environment for the induction of cellular senescence, a mechanism that prioritizes cellular survival at the expense of function and that is often accompanied by a pro-inflammatory secretome that contributes to the maintenance of chronic inflammation [ 6 , 7 ]. Cellular senescence is also considered to be the target of some bacterial pathogens, which can subvert some biological processes for their own benefit ( Figure 1 ).…”

“…In this regard, it has been pointed out that states of both persistent infection and chronic inflammation lead to senescence of T lymphocytes, which play a key role in the pathogenesis of periodontitis, and their activity is strongly associated with the severity of its clinical manifestations [ 9 ]. Mainly, senescence of CD4 + T lymphocytes appears to be a common feature of osteoimmunological diseases, suggesting that CD4 + T cell senescence may also occur in the context of periodontitis [ 7 ]. This review aims to summarize and discuss the evidence regarding pathogenic senescent CD4 + T lymphocytes as a potential mediator in the periodontal microenvironment that contributes to osteoimmunological changes responsible for alveolar bone loss, particularly the Th17/Treg imbalance in periodontitis-affected tissues.…”