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A large body of evidence has established that T cells and cytokine mediators originating from the immune system potently impact bone turnover in both physiologic and pathologic conditions. Indeed, osteoclasts derive from precursors that circulate within the immune compartment; however, new revelations continue to emerge attesting to the depth of integration of the skeletal and immune systems, and the consequences of the immuno-skeletal interface for bone metabolism.

Activated T cells have long been recognized to promote osteoclast formation as a consequence of their capacity to secrete osteoclastogenic cytokines including receptor activator of NF-κB ligand (RANKL)1–5; the RANKL-independent osteoclastogenic cytokines, secreted osteoclastogenic factor of activated T cells (SOFAT)6 and tumor necrosis factor (TNF) ligand superfamily member 14 (TNSF14, or LIGHT),7 and the inflammatory mediator TNFα.8 TNFα stimulates RANKL production in osteoblastic cells9 and potently synergizes with RANKL to intensify osteoclastogenesis8, 10, 11 and resorption.12 Indeed, RANKL and/or TNFα, derived in part from activated T cells, have been implicated in bone loss and joint destruction in animal models of rheumatoid arthritis,13 alveolar bone loss in periodontal infection,14, 15 and in humans and animal models of the archetypal osteoporotic bone disease, postmenopausal osteoporosis.5, 16, 17

Interestingly, although lymphocytes are protagonists of bone loss in inflammatory states, under physiologic conditions both human18 and rodent B cells19, 20 secrete the RANKL decoy receptor osteoprotegerin (OPG), an activity potentiated by T cell costimulation.19 T cells are thus central to the regulation of basal bone turnover as well as protagonists of pathological bone loss.

αβ T Cells: The Centerpiece of the Adaptive Immune Response

  1. Top of page
  2. αβ T Cells: The Centerpiece of the Adaptive Immune Response
  3. γδ T Cells
  4. Vγ9Vδ2 T Cells
  5. Bisphosphonates and Vγ9Vδ2 T Cells
  6. Aminobisphosphonates and Bisphosphonate-Associated Osteonecrosis of the Jaw
  7. Vγ9Vδ2 T Cells and BAONJ
  8. Disclosures
  9. Acknowledgements
  10. References

T cells regulate both cell-mediated and humeral immunity through expression of costimulatory receptors and ligands and by production of cytokines. A hallmark of the adaptive immune response is its ability to mount a vigorous response to a wide range of antigenic challenges. This is achieved by the existence in the body of a vast repertoire of CD4+ and CD8+ T cell clones, each exhibiting reactivity to a single antigen. This specificity is achieved through the T-cell receptor (TCR), a heterodimer that achieves a wide repertoire of unique antigen specificities though a process of extensive gene recombination. The most common and well studied of the TCR groups are the alpha beta (αβ) TCRs, comprising an α chain paired to a β chain. Each αβ TCR heterodimer recognizes a specific unique processed peptide antigen expressed in concert with a major histocompatibility complex (MHC) molecule on an antigen-presenting cell (APC). Whereas CD4+ T cells recognize MHC class II (MHC II)-bearing antigens, CD8+ T cells are reactive to MHC class I (MHC I) complexed peptide antigens. Engagement of antigen/MHC with the TCR and its associated complexes (including CD3 and CD4 or CD8), in the context of appropriate costimulatory signals including CD28, leads to T cell activation, replication (clonal expansion), and differentiation of CD8+ T cells into cytotoxic effector T cells and CD4+ T cells into one of a number of phenotypes including suppressor T cells (regulatory T cells [Tregs]) and T helper (Th) cells. Each Th is characterized by a distinct pattern of cytokine production and mediates distinct immunological functions.21–27

γδ T Cells

  1. Top of page
  2. αβ T Cells: The Centerpiece of the Adaptive Immune Response
  3. γδ T Cells
  4. Vγ9Vδ2 T Cells
  5. Bisphosphonates and Vγ9Vδ2 T Cells
  6. Aminobisphosphonates and Bisphosphonate-Associated Osteonecrosis of the Jaw
  7. Vγ9Vδ2 T Cells and BAONJ
  8. Disclosures
  9. Acknowledgements
  10. References

Although the vast majority of circulating T cells express αβ TCR chains, a subset of T cells expresses a different TCR. These TCRs contain a gamma (γ) chain paired with a delta (δ) chain, to form a γδ TCR heterodimer and giving rise to a population of γδ T cells. γδ T cells represent only 1% to 10% of nucleated cells in the human peripheral circulation, although their numbers are more abundant in tissues, in particular epithelial tissues such as the skin, where γδ T cells may represent the dominant T cell population.28

γδ T cells are dissimilar to αβ T cells in that their function is largely innate-like rather than adaptive and TCR specificity is directed almost exclusively toward nonpeptide antigens. These “unconventional” T cells can rapidly respond to antigen engagement and are not constrained by the need for clonal expansion or de novo differentiation, as is the case with αβ T cells.28, 29 Like other members of the innate immune response γδ T cells may rapidly engage life-threatening microbial or host-derived pathogens and have been implicated in responses to inflammation, allergy, autoimmunity, infectious disease,28 and certain hematological tumors.28, 30 γδ T cells may further act to regulate the nature and scale of downstream adaptive responses, thus mediating a biological integration of unconventional (γδ) and conventional (αβ) T cells.23, 28

Vγ9Vδ2 T Cells

  1. Top of page
  2. αβ T Cells: The Centerpiece of the Adaptive Immune Response
  3. γδ T Cells
  4. Vγ9Vδ2 T Cells
  5. Bisphosphonates and Vγ9Vδ2 T Cells
  6. Aminobisphosphonates and Bisphosphonate-Associated Osteonecrosis of the Jaw
  7. Vγ9Vδ2 T Cells and BAONJ
  8. Disclosures
  9. Acknowledgements
  10. References

Rather than representing a single population, γδ T cells have been found to be quite heterogeneous. Although, found only in humans and higher primates, Vγ9Vδ2 T cells are a major subpopulation of γδ T cells and are unique in their recognition of low–molecular-weight nonpeptide antigens, often referred to as “phosphoantigens.” These phosphoantigens include metabolites derived from microbial isoprenoid biosynthesis and thus allow Vγ9Vδ2 T cells to respond rapidly to a range of diverse pathogens, including Mycobacterium tuberculosis and Plasmodium falciparum.31

Bisphosphonates and Vγ9Vδ2 T Cells

  1. Top of page
  2. αβ T Cells: The Centerpiece of the Adaptive Immune Response
  3. γδ T Cells
  4. Vγ9Vδ2 T Cells
  5. Bisphosphonates and Vγ9Vδ2 T Cells
  6. Aminobisphosphonates and Bisphosphonate-Associated Osteonecrosis of the Jaw
  7. Vγ9Vδ2 T Cells and BAONJ
  8. Disclosures
  9. Acknowledgements
  10. References

An interesting and pertinent finding for bone biology is that Vγ9Vδ2 T cells are indirectly activated by one of the most commonly prescribed antiresorptive drug classes used in osteoporosis management, nitrogen-bisphosphonates (n-BPs), also referred to as aminobisphosphonates. It has further been proposed that the activation of γδ T cells, with a consequent release of cytokines such as interferon γ (IFNγ), might contribute to the acute-phase reaction that is commonly observed following the first infusion of an aminobisphosphonate.32 Interestingly, repeated exposure to n-BPs appears to desensitize patients from acute-phase reactions, and a recent study suggest that this may be a consequence of a chronic decline in circulating γδ T cells following initial exposure to both oral and intravenous n-BPs.33

The exact mechanism of γδ T cell activation by n-BPs remains unclear, but it has been suggested that n-BPs share structural homologies with phosphoantigens, the traditional γδ T cell ligands, thus activating γδ T cells though direct association with γδ receptors.30 Interestingly, later studies revealed that whereas aminobisphosphonates, including pamidronate, ibandronate, and alendronate, activate Vγ9Vδ2 T cells, non–n-BPs, such as clodronate and etidronate, do not provoke Vγ9Vδ2 reactivity.32 These observations have led to speculation that because n-BPs are potent inhibitors of the mevalonate pathway, n-BPs may lead to accumulation of the phosphoantigen isopentenyl pyrophosphate and its stereoisomer dimethylallyl diphosphate, powerful microbiological “danger” signals that could render cells the targets of Vγ9Vδ2 attack.31, 34, 35 Because non–nitrogen containing bisphosphonates function through a different biochemical pathway, this hypothesis provides a possible explanation for why only n-BPs activate γδ T cells whereas non–nitrogen containing bisphosphonates are inactive, despite greater homology to isopentenyl pyrophosphate, a molecule that itself is devoid of nitrogen in its structure. Adding additional complexity, studies have revealed that the presence of monocytes is essential for the n-BP pamidronate to activate γδ T cells in culture, suggesting that monocytes may need to present aminobisphosphonate antigens to γδ T cells.36 In support of this hypothesis, peripheral blood monocytes have been implicated in the activation of γδ T cells, by zoledronic acid, in a cell contact–dependent manner that involved accumulation of isopentenyl pyrophosphate and dimethylallyl diphosphate.35

Aminobisphosphonates and Bisphosphonate-Associated Osteonecrosis of the Jaw

  1. Top of page
  2. αβ T Cells: The Centerpiece of the Adaptive Immune Response
  3. γδ T Cells
  4. Vγ9Vδ2 T Cells
  5. Bisphosphonates and Vγ9Vδ2 T Cells
  6. Aminobisphosphonates and Bisphosphonate-Associated Osteonecrosis of the Jaw
  7. Vγ9Vδ2 T Cells and BAONJ
  8. Disclosures
  9. Acknowledgements
  10. References

Aminobisphosphonates are among the most potent and frequently prescribed antiresorptive agents for the management of osteoporosis. Bisphosphonate-associated (BA) osteonecrosis of the jaw (ONJ) is a rare but serious side effect of chronic bisphosphonate therapy. The consequences of BAONJ are not trivial and the associated pain, difficulties in performing oral hygiene and eating, can severely affect patient quality of life.37

ONJ is defined as the presence of exposed bone in the maxillofacial region that does not heal within 8 weeks after identification by a health care provider.38 Although BAONJ may occur spontaneously, it is most frequently associated with invasive dental procedures such as surgeries and tooth extractions. The risk of ONJ from oral bisphosphonate therapy is uncertain, but it is generally considered to be low, with estimates of between 1 in 10,000 and <1 in 100,000 patient–treatment years. Use of high-dose intravenous bisphosphonates in cancer patients, however, has a markedly higher incidence of ONJ ranging between 1% and 10%.38

Vγ9Vδ2 T Cells and BAONJ

  1. Top of page
  2. αβ T Cells: The Centerpiece of the Adaptive Immune Response
  3. γδ T Cells
  4. Vγ9Vδ2 T Cells
  5. Bisphosphonates and Vγ9Vδ2 T Cells
  6. Aminobisphosphonates and Bisphosphonate-Associated Osteonecrosis of the Jaw
  7. Vγ9Vδ2 T Cells and BAONJ
  8. Disclosures
  9. Acknowledgements
  10. References

In this issue of the Journal of Bone and Mineral Research, a new observational clinical study by Kalyan and colleagues39 reveals a number of intriguing associations between BAONJ and Vγ9Vδ2 T cells.

In this study the fate of Vγ9Vδ2 T-cells in osteoporotic patients on n-BP therapy was assessed as a function of time and administration route. Although no difference was observed in total peripheral T cells (or in monocytes or granulocytes), the authors reported a loss of Vγ9Vδ2 T cells over a 6-year period in osteoporotic patients on oral n-BPs and an even more striking decline in γδ T cells in patients administered intravenous n-BPs, resulting in significant deficiency after just 1 year of treatment.

These findings are in good agreement with a very recent study by Rossini and colleagues,33 who reported a significant and permanent reduction in γδ T cells, in terms of both proportion and absolute number, following infusion of zoledronic acid.

Kalyan and colleagues39 further documented a significant deficiency in Vγ9Vδ2 T cells in comparison to age- and sex-matched treatment naïve controls, in six patients who had recently experienced BAONJ. Importantly, all patients who experienced BAONJ were found to have an underlying condition that further contributed to disrupted immunity, including three patients under treatment for breast cancer, one for hematological malignancy, and one for hepatitis B and C infection.

Interestingly, in the control non-BAONJ group, study exclusion criteria included patients on immunomodulatory agents and enrolment was limited to postmenopausal women (97%) and men with senile osteoporosis (3%). Both estrogen deficiency and advanced age are associated with heightened states of immune activation and a chronic low-level inflammation. It is tempting to speculate that this low-grade immune activation may be protective of BAONJ in postmenopausal and aging patients. BAONJ may thus be largely associated with immunocompromised patients. In fact, a reported higher risk for ONJ has been reported in patients with human immunodeficiency virus (HIV),40, 41 as well as a significant decline in γδ T cells.42 The authors further speculate as to whether this increased susceptibility to ONJ in HIV patients has any association with the loss of γδ T cells within the backdrop of immunodeficiency. Given the significant incidence of osteopenia and osteoporosis and high rates of bone fracture observed in the HIV+ population43, 44 more frequent use of n-BPs in aging (and even younger) HIV patients in the future is highly likely and BAONJ could become a significant concern.

The mechanism by which immune surveillance may mitigate BAONJ is still unclear. Although the presence of oral bacteria have been associated with the development of BAONJ following tooth extraction in n-BP–treated mice,45 and may be present in human BAONJ,38 it remains unclear if oral bacteria are premeditating in humans or if bacterial invasion is a downstream consequence of tissue degradation and weak immunity.

One potential caveat to be considered is that n-BPs are not the only antiosteoporotic agents associated with ONJ. Recent studies in metastatic bone cancer patients have revealed that the RANKL antagonist denosumab is also associated with ONJ and with incidence at least as high as that of n-BPs.46 As both agents lead to a low bone-turnover state that is likely propitious for development of ONJ, it might be concluded that suppressed bone turnover by anticatabolic drugs in general may be the overriding determinant for ONJ development. However, even if low bone turnover were the initiating event, subsequent microbial invasion may exacerbate the sequelae, an event potentially combated by γδ T cells.

Although RANKL is directly involved in T cell costimulatory processes,47 it is possible that denosumab depletion of RANKL itself has an impact on immune function in the context of γδ T cells. Furthermore, RANKL has recently been demonstrated to be necessary for thymic selection during development of γδ T-cell progenitors.48 Consequently, while n-BPs may lead to γδ T cell depletion though chronic activation and activation induced cell death (ACID), it is not inconceivable that suppression of RANKL by denosumab may indirectly alter γδ T-cell subsets by reducing T cell development de novo and/or by lowering immune defenses against microbial invasion of bone tissues though diminished antigen presentation. These mechanistic issues remain to be addressed in future studies.

In conclusion, Kalyan and colleagues39 speculate that “Vγ9Vδ2 T-cells show a strong potential to serve as harbingers of possible adverse immune affects of n-BP therapy—particularly in those patients already having a compromised immune system as they may be most vulnerable to the development of conditions such as BAONJ.” Cancer, HIV-infected, and other immunocompromised patients thus may be predisposed to BAONJ.

Presently, lack of a clear underlying basis for BAONJ, coupled with the lack of a murine counterpart for Vγ9Vδ2 T cells, significantly complicates mechanistic investigations given the limitations of human studies. Although these correlative studies suggest a tantalizing possible association between γδ T cells and development of BAONJ, further mechanistic studies are needed to establish a direct cause-effect relationship and to explain the basis for how Vγ9Vδ2 T cells may provide protection from development of ONJ. Should such data be forthcoming, studies to define therapeutic approaches to limit loss of, or to regenerate γδ T cells following antiresorptive therapy, may become an important future endeavor.

Acknowledgements

  1. Top of page
  2. αβ T Cells: The Centerpiece of the Adaptive Immune Response
  3. γδ T Cells
  4. Vγ9Vδ2 T Cells
  5. Bisphosphonates and Vγ9Vδ2 T Cells
  6. Aminobisphosphonates and Bisphosphonate-Associated Osteonecrosis of the Jaw
  7. Vγ9Vδ2 T Cells and BAONJ
  8. Disclosures
  9. Acknowledgements
  10. References

The author gratefully acknowledges support from the Biomedical Laboratory Research & Development Service of the VA Office of Research and Development (5I01BX000105) and by NIH grants from NIAMS (R01AR056090 and R01AR059364) and the NIA (R01AG040013).

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  2. αβ T Cells: The Centerpiece of the Adaptive Immune Response
  3. γδ T Cells
  4. Vγ9Vδ2 T Cells
  5. Bisphosphonates and Vγ9Vδ2 T Cells
  6. Aminobisphosphonates and Bisphosphonate-Associated Osteonecrosis of the Jaw
  7. Vγ9Vδ2 T Cells and BAONJ
  8. Disclosures
  9. Acknowledgements
  10. References
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