{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T02:18:30Z","timestamp":1793067510660,"version":"4.5.0"},"reference-count":123,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T00:00:00Z","timestamp":1781222400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Osteoporosis weakens the skeleton by lowering bone mass and damaging bone microarchitecture. A growing body of evidence points to disruptions in osteoimmune homeostasis as a key driver of this disease. In particular, apoptosis of bone cells and immune cells appears to be a critical contributing mechanism. Within the bone marrow, CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells display a surprising functional duality: whether they protect bone or promote its loss depends heavily on local signals. Under healthy conditions or after mechanical loading, activated CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells help maintain bone mass. They do so mainly by secreting interferon\u2011\u03b3 (IFN\u2011\u03b3), which blocks osteoclast formation through interference with NF\u2011\u03baB and MAPK signaling. However, this protective role is not fixed. Pathological cues such as estrogen deficiency can flip CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells into a bone\u2011destroying phenotype. For example, when estrogen drops, muscle\u2011derived IL\u201133 decreases. That drop prompts bone marrow CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells to release large amounts of CCL5. CCL5 then binds to CCR3 on osteoclast precursors and activates the ERK pathway, thereby accelerating bone loss in postmenopausal osteoporosis. Aging and chronic inflammation add another layer of complexity. They drive the accumulation of senescent CD28\n                      <jats:sup>-<\/jats:sup>\n                      CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells. These aged cells no longer produce enough IFN\u2011\u03b3 to protect bone; instead, they adopt a senescence\u2011associated secretory phenotype (SASP) that suppresses osteoblast differentiation and reduces mesenchymal stromal cell viability. Moreover, apoptosis of osteoblasts and osteocytes\u2014triggered by TNF\u2011\u03b1, IFN\u2011\u03b3, or glucocorticoids\u2014worsens bone loss. New findings suggest that CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells may fuel this apoptotic process through Fas\/FasL interactions and the granzyme\/perforin pathway. This review brings together these context\u2011dependent mechanisms. We place special emphasis on how hormonal shifts, metabolic changes, and inflammatory mediators converge to decide whether CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells support skeletal integrity or drive bone resorption.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We performed a narrative review of recent studies on CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells in osteoporosis. We searched PubMed and Web of Science using keywords such as \u201costeoporosis\u201d, \u201costeoimmunology\u201d, \u201cCD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells\u201d, \u201cIFN\u2011\u03b3\u201d, \u201cCCL5\u201d, \u201ccellular senescence\u201d, \u201cSASP\u201d, \u201cFas\/FasL\u201d, and \u201cgranzyme\u201d. From the retrieved articles, we selected original research (including\n                      <jats:italic>in vitro<\/jats:italic>\n                      co\u2011culture systems, animal models, and clinical samples) and relevant reviews. We then extracted and integrated key mechanistic evidence regarding the dual functionality of CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells and its regulatory pathways.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells have two opposing functions. Under healthy conditions or mechanical loading, activated CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells secrete IFN\u2011\u03b3, which inhibits osteoclast formation by interfering with NF\u2011\u03baB and MAPK signaling, thus maintaining bone mass. In contrast, when estrogen is deficient, reduced muscle\u2011derived IL\u201133 causes bone marrow CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells to release large amounts of CCL5. CCL5 binds to CCR3 on osteoclast precursors and activates the ERK pathway, accelerating bone loss. Aging and chronic inflammation shift the balance. Aging and chronic inflammation lead to the accumulation of senescent CD28\n                      <jats:sup>-<\/jats:sup>\n                      CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells. These cells no longer produce sufficient protective IFN\u2011\u03b3. Instead, they exhibit a senescence\u2011associated secretory phenotype (SASP) that suppresses osteoblast differentiation and reduces mesenchymal stromal cell viability. CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells may promote bone cell apoptosis through multiple pathways. TNF\u2011\u03b1, IFN\u2011\u03b3, or glucocorticoids can trigger apoptosis of osteoblasts and osteocytes. Newer evidence suggests that CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells amplify this process via Fas\/FasL interactions and the granzyme\/perforin pathway. Two newly identified CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell\u2011derived molecules deserve attention. Granzyme K protects against bone loss, whereas CCL5 promotes bone loss. These two molecules offer fresh opportunities for biomarkers and therapies.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      Our synthesis shows that CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells act as a double\u2011edged sword in osteoporosis: their functional switch depends on the integration of hormonal, metabolic, and inflammatory signals. Under normal conditions or after mechanical loading, the anti\u2011osteoclastogenic effect of IFN\u2011\u03b3 dominates. But when estrogen levels fall, the IL\u201133\/CCL5\/CCR3\/ERK axis becomes activated, turning CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells toward a bone\u2011resorbing phenotype. During aging, the buildup of CD28\u207b CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells and their SASP further weakens bone formation and worsens bone cell death through apoptotic pathways. These observations point to a more precise therapeutic strategy. Instead of broadly modulating T cells, one could specifically target pathogenic pathways\u2014for example, by interfering with the IL 33\/ST2\/CCL5 cascade or by clearing immune senescent CD28\u207b subsets. Such approaches might help restore osteoimmune balance. Two recently discovered CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell derived molecules, granzyme K and CCL5, are particularly interesting because they respectively protect against and promote bone loss. They could serve as novel biomarkers or even therapeutic targets. Future studies should examine the cell type specific regulation of these pathways in vivo and test the safety and efficacy of targeted interventions.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1874242","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T04:46:46Z","timestamp":1781239606000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["The role of CD8+ T cells in the immunoregulation of osteoporosis"],"prefix":"10.3389","volume":"17","author":[{"given":"ZiChao","family":"Chen","sequence":"first","affiliation":[{"name":"Organization Kunming Calmette International Hospital","place":["KunMing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Hu","sequence":"additional","affiliation":[{"name":"Organization Xiangnan University","place":["ChenZhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Die","family":"Hu","sequence":"additional","affiliation":[{"name":"Organization Hunan University of Medicine","place":["HuaiHua, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"QinChuan","family":"Du","sequence":"additional","affiliation":[{"name":"Organization Kunming Calmette International Hospital","place":["KunMing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"HuanZhi","family":"Yang","sequence":"additional","affiliation":[{"name":"Organization Kunming Calmette International Hospital","place":["KunMing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"RongHua","family":"Xu","sequence":"additional","affiliation":[{"name":"Organization Kunming Calmette International Hospital","place":["KunMing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Yu","sequence":"additional","affiliation":[{"name":"Organization Kunming Calmette International Hospital","place":["KunMing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"XingBo","family":"Hu","sequence":"additional","affiliation":[{"name":"Organization Kunming Calmette International Hospital","place":["KunMing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Hu","sequence":"additional","affiliation":[{"name":"Organization Kunming Calmette International Hospital","place":["KunMing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1698283","article-title":"Functional roles of immune cells in osteoporosis","volume":"16","author":"Qi","year":"2025","journal-title":"Front Immunol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3389\/fpubh.2025.1601892","article-title":"Health outcomes and care needs after osteoporotic fractures in rural Chinese older adults: policy implications","volume":"13","author":"Zhu","year":"2025","journal-title":"Front Public Health"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.17179\/excli2020-2591","article-title":"Osteoporosis: Pathophysiology and therapeutic options","volume":"19","author":"F\u00f6ger-Samwald","year":"2020","journal-title":"Excli J"},{"key":"B4","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1007\/s12016-025-09046-1","article-title":"Osteoimmunology: Crosstalk between T cells and osteoclasts in osteoporosis","volume":"68","author":"Lu","year":"2025","journal-title":"Clin Rev Allergy Immunol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1007\/s00774-024-01539-x","article-title":"Crosstalk between bone and the immune system","volume":"42","author":"Okamoto","year":"2024","journal-title":"J Bone Miner Metab"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2020.00465","article-title":"Osteoimmunology: The regulatory roles of T lymphocytes in osteoporosis","volume":"11","author":"Zhang","year":"2020","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2025.116909","article-title":"CD8(+) T cell-based immunotherapy: Promising frontier in human diseases","volume":"237","author":"Ton Nu","year":"2025","journal-title":"Biochem Pharmacol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.14336\/ad.2021.0110","article-title":"Premature senescence of T-cells favors bone loss during osteolytic diseases. A new concern in the osteoimmunology arena","volume":"12","author":"Gonz\u00e1lez-Osuna","year":"2021","journal-title":"Aging Dis"},{"key":"B9","doi-asserted-by":"publisher","first-page":"2030818","DOI":"10.1155\/2022\/2030818","article-title":"Wheel-running exercise protects ovariectomized mice from bone loss via IFN-\u03b3-mediated suppression of the NF-\u03baB and MAPK pathways","volume":"2022","author":"Shen","year":"2022","journal-title":"Oxid Med Cell Longev"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1600253","article-title":"Osteoclast-primed Foxp3+ CD8 T cells induce T-bet, Eomesodermin, and IFN-\u03b3 to regulate bone resorption","volume":"197","author":"Shashkova","year":"2016","journal-title":"J Immunol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.2217\/imt-2021-0282","article-title":"Immunology of osteoporosis: relevance of inflammatory targets for the development of novel interventions","volume":"14","author":"Ahmad","year":"2022","journal-title":"Immunotherapy"},{"key":"B12","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1007\/s00223-025-01402-9","article-title":"CD8a\u2009+\u2009GZMK\u2009+\u2009T cells inhibit osteoclastogenesis in postmenopausal osteoporosis via the p38-MAPK pathway","volume":"116","author":"He","year":"2025","journal-title":"Calcif Tissue Int"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1155\/2022\/3337622","article-title":"Effect of lymphocyte subsets on bone density in senile osteoporosis: A retrospective study","volume":"2022","author":"Peng","year":"2022","journal-title":"J Immunol Res"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.7754\/clin.lab.2020.191238","article-title":"Risk interval of complete blood counts may be closely associated with bone mineral density in the elderly Chinese population","volume":"66","author":"Ou-Yang","year":"2020","journal-title":"Clin Lab"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1002\/jbm4.10636\/v2\/response1","article-title":"Cyclic adenosine monophosphate (cAMP)-dependent phosphodiesterase inhibition promotes bone anabolism through CD8(+) T cell Wnt-10b production in mice","volume":"6","author":"Roser-Page","year":"2022","journal-title":"JBMR Plus"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.jot.2025.06.015","article-title":"Immunoporosis: The hidden link between aging immune cells and bone fragility","volume":"53","author":"Cheng","year":"2025","journal-title":"J Orthop Translat"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2021.116014","article-title":"CD8(+) T cells from experimental in situ breast carcinoma interfere with bone homeostasis","volume":"150","author":"Monteiro","year":"2021","journal-title":"Bone"},{"key":"B18","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1016\/j.jot.2024.12.004","article-title":"T cell related osteoimmunology in fracture healing: Potential targets for augmenting bone regeneration","volume":"51","author":"Wang","year":"2025","journal-title":"J Orthop Translat"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2022.990769","article-title":"Repair of bone defects in rhesus monkeys with \u03b11,3-galactosyltransferase-knockout pig cancellous bone","volume":"10","author":"Wang","year":"2022","journal-title":"Front Bioeng Biotechnol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1476009","article-title":"Prognostic implications of a CD8(+) T(EMRA) to CD4(+)T(reg) imbalance in mandibular fracture healing: a prospective analysis of immune profiles","volume":"15","author":"Voss","year":"2024","journal-title":"Front Immunol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1093\/jbmrpl\/ziae101","article-title":"IL-33 prevents age-related bone loss and memory impairment by suppression of Th17 response: evidence in a d-galactose-induced aging mouse model","volume":"8","author":"Kaushal","year":"2024","journal-title":"JBMR Plus"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1172\/jci11066","article-title":"Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-alpha","volume":"106","author":"Cenci","year":"2000","journal-title":"J Clin Invest"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1128\/spectrum.02726-24","article-title":"When estrogen deficiency meets immune responses induced by rabies vaccination","volume":"13","author":"Qian","year":"2025","journal-title":"Microbiol Spectr"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1002\/med.22081","article-title":"Estrogen deficiency-mediated osteoimmunity in postmenopausal osteoporosis","volume":"45","author":"Yao","year":"2025","journal-title":"Med Res Rev"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2021.102224","article-title":"Mice lacking DKK1 in T cells exhibit high bone mass and are protected from estrogen-deficiency-induced bone loss","volume":"24","author":"Lehmann","year":"2021","journal-title":"iScience"},{"key":"B26","doi-asserted-by":"publisher","first-page":"25","DOI":"10.5312\/WJO.v2.i3.25","article-title":"Interactions between the immune system and bone","volume":"2","author":"D'Amelio","year":"2011","journal-title":"World J Orthop"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2025.152212","article-title":"Estrogen deficiency impairs double-negative T cell function and activates NF-\u03baB in postmenopausal osteoporosis","volume":"776","author":"Jin","year":"2025","journal-title":"Biochem Biophys Res Commun"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2025.106024","article-title":"Skeletal muscle-derived IL-33 mediates muscle-to-bone crosstalk and regulates bone metabolism via CD8(+) T cell-secreted CCL5","volume":"122","author":"Liu","year":"2025","journal-title":"EBioMedicine"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2025.106073","article-title":"IL-33: targeting a muscle-to-bone signaling axis in osteosarcopenia","volume":"123","author":"Abdullah","year":"2026","journal-title":"EBioMedicine"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1210\/en.2005-0065","article-title":"Functional expression of beta-chemokine receptors in osteoblasts: role of regulated upon activation, normal T cell expressed and secreted (RANTES) in osteoblasts and regulation of its secretion by osteoblasts and osteoclasts","volume":"146","author":"Yano","year":"2005","journal-title":"Endocrinology"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2025.114753","article-title":"ST1936 stimulates osteoclastogenesis and suppresses osteoclastic apoptosis through the ERK1\/2 signaling pathway in bone marrow-derived macrophages","volume":"157","author":"Yun","year":"2025","journal-title":"Int Immunopharmacol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.1500","article-title":"Role of T cells in ovariectomy induced bone loss--revisited","volume":"27","author":"Pacifici","year":"2012","journal-title":"J Bone Miner Res"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.833531","article-title":"Co-expression of TIGIT and Helios marks immunosenescent CD8(+) T cells during aging","volume":"13","author":"Pieren","year":"2022","journal-title":"Front Immunol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13607","article-title":"Epigenetic quantification of immunosenescent CD8(+) TEMRA cells in human blood","volume":"21","author":"Salumets","year":"2022","journal-title":"Aging Cell"},{"key":"B35","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1186\/s12981-021-00361-z","article-title":"Assessing the differential impact of chronic CMV and treated HIV infection on CD8+ T-cell differentiation in a matched cohort study: is CMV the key","volume":"18","author":"Mueller","year":"2021","journal-title":"AIDS Res Ther"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1139517","article-title":"Loss of CD28 expression associates with severe T-cell exhaustion in acute myeloid leukemia","volume":"14","author":"Huang","year":"2023","journal-title":"Front Immunol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1891\/9780826145987.0003","article-title":"CD8(+)CD57(+) T cells exhibit distinct features in human non-small cell lung cancer","volume":"8","author":"Huang","year":"2020","journal-title":"J Immunother Cancer"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.7754\/clin.lab.2023.231215","article-title":"Research and analysis of molecules such as CD28, CD45RA, CD45RO, CD38, HLA-DR, and CD57 on T cells in multiple myeloma","volume":"70","author":"Yang","year":"2024","journal-title":"Clin Lab"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1007\/s00198-011-1650-x","article-title":"Premature T cell senescence in Ovx mice is inhibited by repletion of estrogen and medicarpin: a possible mechanism for alleviating bone loss","volume":"23","author":"Tyagi","year":"2012","journal-title":"Osteoporos Int"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.exger.2003.09.024","article-title":"Replicative senescence of CD8 T cells: effect on human ageing","volume":"39","author":"Effros","year":"2004","journal-title":"Exp Gerontol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2014-206119","article-title":"Premature senescence of T-cell subsets in axial spondyloarthritis","volume":"75","author":"Fessler","year":"2016","journal-title":"Ann Rheum Dis"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.14336\/ad.2024.0219","article-title":"Senescent T cells in age-related diseases","volume":"16","author":"Yu","year":"2024","journal-title":"Aging Dis"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-025-01347-1","article-title":"Targeting MondoA-TXNIP restores antitumour immunity in lactic-acid-induced immunosuppressive microenvironment","volume":"7","author":"Xu","year":"2025","journal-title":"Nat Metab"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3389\/fragi.2021.681428","article-title":"Altered nutrient uptake causes mitochondrial dysfunction in senescent CD8(+) EMRA T cells during type 2 diabetes","volume":"2","author":"Callender","year":"2021","journal-title":"Front Aging"},{"key":"B45","doi-asserted-by":"publisher","first-page":"8153","DOI":"10.1038\/s41598-024-59062-y","article-title":"Development and experimental validation of an energy metabolism-related gene signature for diagnosing of osteoporosis","volume":"14","author":"Lu","year":"2024","journal-title":"Sci Rep"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1095195","article-title":"A chemokine network of T cell exhaustion and metabolic reprogramming in renal cell carcinoma","volume":"14","author":"Pichler","year":"2023","journal-title":"Front Immunol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.2174\/0113862073350964241203080017","article-title":"Identification of mitochondrial-related characteristic biomarkers in osteosarcoma using bioinformatics and machine learning","author":"Hou","year":"2025","journal-title":"Comb Chem High Throughput Screen"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1172\/jci140100","article-title":"Selective glutamine metabolism inhibition in tumor cells improves antitumor T lymphocyte activity in triple-negative breast cancer","volume":"131","author":"Edwards","year":"2021","journal-title":"J Clin Invest"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.can-24-3477","article-title":"Blocking the TCA cycle in cancer cells potentiates CD36+ T-cell-mediated antitumor immunity by suppressing ER stress-associated THBS2 signaling","volume":"85","author":"Yang","year":"2025","journal-title":"Cancer Res"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-024-01037-4","article-title":"Acetate reprogrammes tumour metabolism and promotes PD-L1 expression and immune evasion by upregulating c-Myc","volume":"6","author":"Wang","year":"2024","journal-title":"Nat Metab"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2024.111549","article-title":"Targeting p38 MAPK: A potential bridge between ER stress and age-related bone loss","volume":"127","author":"Yin","year":"2025","journal-title":"Cell Signal"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1007\/s10787-015-0233-4","article-title":"Effect of bisphosphonates treatment on cytokine imbalance between TH17 and Treg in osteoporosis","volume":"23","author":"Talaat","year":"2015","journal-title":"Inflammopharmacology"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2021.790613","article-title":"Comparison of necroptosis with apoptosis for OVX-induced osteoporosis","volume":"8","author":"He","year":"2021","journal-title":"Front Mol Biosci"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2024.117050","article-title":"TNF-\u03b1 promotes osteocyte necroptosis by upregulating TLR4 in postmenopausal osteoporosis","volume":"182","author":"Cui","year":"2024","journal-title":"Bone"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0150805","article-title":"The RIP1-RIP3 complex mediates osteocyte necroptosis after ovariectomy in rats","volume":"11","author":"Cui","year":"2016","journal-title":"PLoS One"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1038\/srep33803","article-title":"Necrostatin-1 treatment inhibits osteocyte necroptosis and trabecular deterioration in ovariectomized rats","volume":"6","author":"Cui","year":"2016","journal-title":"Sci Rep"},{"key":"B57","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1038\/s41419-020-03249-4","article-title":"The critical role of T cells in glucocorticoid-induced osteoporosis","volume":"12","author":"Song","year":"2020","journal-title":"Cell Death Dis"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1172\/jci166795","article-title":"Excess glucocorticoids inhibit murine bone turnover via modulating the immunometabolism of the skeletal microenvironment","volume":"134","author":"Li","year":"2024","journal-title":"J Clin Invest"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1097\/md.0000000000042668","article-title":"Advances in the study and treatment of glucocorticoid osteoporosis: A review","volume":"104","author":"Song","year":"2025","journal-title":"Med (Baltimore)"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00657","article-title":"Immunoporosis: Immunology of osteoporosis-role of T cells","volume":"9","author":"Srivastava","year":"2018","journal-title":"Front Immunol"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1800697","article-title":"High-dose IL-2 skews a glucocorticoid-driven IL-17(+)IL-10(+) memory CD4(+) T cell response towards a single IL-10-producing phenotype","volume":"202","author":"Mann","year":"2019","journal-title":"J Immunol"},{"key":"B62","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1038\/s41413-025-00456-7","article-title":"Unraveling the mechanisms of bone diseases: Targeting dendritic cells in osteoimmunology for internal homeostasis balance","volume":"13","author":"Chen","year":"2025","journal-title":"Bone Res"},{"key":"B63","doi-asserted-by":"publisher","first-page":"177ra36","DOI":"10.1126\/scitranslmed.3004754","article-title":"Terminally differentiated CD8+ T cells negatively affect bone regeneration in humans","volume":"5","author":"Reinke","year":"2013","journal-title":"Sci Transl Med"},{"key":"B64","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1186\/s12979-022-00290-z","article-title":"Evaluation of T-cell aging-related immune phenotypes in the context of biological aging and multimorbidity in the Health and Retirement Study","volume":"19","author":"Ramasubramanian","year":"2022","journal-title":"Immun Ageing"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1016\/j.exger.2007.06.008","article-title":"The immune system in extreme longevity","volume":"43","author":"Sansoni","year":"2008","journal-title":"Exp Gerontol"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.3389\/fragi.2026.1765665","article-title":"Phenotypic and functional heterogeneity of na\u00efve CD8(+) T cells in human peripheral blood during aging","volume":"7","author":"Pangrazzi","year":"2026","journal-title":"Front Aging"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23052543","article-title":"Senescent CD4(+)CD28(-) T lymphocytes as a potential driver of Th17\/Treg imbalance and alveolar bone resorption during periodontitis","volume":"23","author":"Gonz\u00e1lez-Osuna","year":"2022","journal-title":"Int J Mol Sci"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2005.02.001","article-title":"Protective effects of a traditional Chinese medicine, You-Gui-Wan, on steroid-induced inhibition of cytokine production in mice","volume":"5","author":"Yao","year":"2005","journal-title":"Int Immunopharmacol"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.ra119.008074","article-title":"IL-6 exhibits both cis- and trans-signaling in osteocytes and osteoblasts, but only trans-signaling promotes bone formation and osteoclastogenesis","volume":"294","author":"McGregor","year":"2019","journal-title":"J Biol Chem"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.2174\/18735592mtawhmzkdy","article-title":"TNF-\u03b1 and IL-6: The link between immune and bone system","volume":"21","author":"Wang","year":"2020","journal-title":"Curr Drug Targets"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2006.117382","article-title":"Gut, inflammation and osteoporosis: Basic and clinical concepts","volume":"57","author":"Tilg","year":"2008","journal-title":"Gut"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1177\/1759720x12441275","article-title":"Biologicals and bone loss","volume":"4","author":"Krieckaert","year":"2012","journal-title":"Ther Adv Musculoskelet Dis"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.2174\/0113862073273655231213070619","article-title":"Disulfidptosis-related protein RPN1 may be a novel anti-osteoporosis target of kaempferol","volume":"27","author":"Pan","year":"2024","journal-title":"Comb Chem High Throughput Screen"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2025.1609915","article-title":"Identification of shared diagnostic genes between osteoporosis and Crohn's disease through integrated transcriptomic analysis and machine learning","volume":"16","author":"Yi","year":"2025","journal-title":"Front Genet"},{"key":"B75","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1007\/s00774-018-0965-5","article-title":"Clinical immunity in bone and joints","volume":"37","author":"Tanaka","year":"2019","journal-title":"J Bone Miner Metab"},{"key":"B76","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1111\/nyas.14518","article-title":"Absence of \u03b1\u03b2 T cells accelerates disuse bone loss in male mice after spinal cord injury","volume":"1487","author":"Sahbani","year":"2021","journal-title":"Ann N Y Acad Sci"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/429373","article-title":"Osteoclasts and CD8 T cells form a negative feedback loop that contributes to homeostasis of both the skeletal and immune systems","volume":"2013","author":"Buchwald","year":"2013","journal-title":"Clin Dev Immunol"},{"key":"B78","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1016\/j.bbmt.2008.11.038","article-title":"Immune reconstitution following myeloablative allogeneic hematopoietic stem cell transplantation: The impact of expanding CD28negative CD8+ T cells on relapse","volume":"15","author":"Yakoub-Agha","year":"2009","journal-title":"Biol Blood Marrow Transplant"},{"key":"B79","doi-asserted-by":"publisher","first-page":"798","DOI":"10.1016\/j.ard.2025.01.022","article-title":"Dysfunctional KLRB1(+)CD8(+) T-cell responses are generated in chronically inflamed systemic sclerosis skin","volume":"84","author":"Gaydosik","year":"2025","journal-title":"Ann Rheum Dis"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2024.113357","article-title":"Study of kaempferol in the treatment of rheumatoid arthritis through modulation of the NLRP3\/CASP1\/GSDMD axis and T-cell activation: Based on network pharmacology, single-cell analysis, and experimental validation","volume":"143","author":"He","year":"2024","journal-title":"Int Immunopharmacol"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1093\/jbmr\/zjaf055","article-title":"Programmed cell death protein 1 (PD-1) blockade regulates skeletal remodeling in a sex- and age-dependent manner","volume":"40","author":"Joseph","year":"2025","journal-title":"J Bone Miner Res"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbmt.2020.07.001","article-title":"Bone health management after hematopoietic cell transplantation: An expert panel opinion from the American Society for Transplantation and Cellular Therapy","volume":"26","author":"Bar","year":"2020","journal-title":"Biol Blood Marrow Transplant"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20201730","article-title":"The architectural design of CD8+ T cell responses in acute and chronic infection: Parallel structures with divergent fates","volume":"218","author":"Chung","year":"2021","journal-title":"J Exp Med"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.4110\/in.2023.23.e2","article-title":"Shaping heterogeneity of naive CD8(+) T cell pools","volume":"23","author":"Lee","year":"2023","journal-title":"Immune Netw"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.3390\/cancers8030036","article-title":"Different subsets of T cells, memory, effector functions, and CAR-T immunotherapy","volume":"8","author":"Golubovskaya","year":"2016","journal-title":"Cancers (Basel)"},{"key":"B86","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/j.imlet.2017.10.002","article-title":"Current perspectives on the role of CD8+ T cells in systemic sclerosis","volume":"195","author":"Fuschiotti","year":"2018","journal-title":"Immunol Lett"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1542531","article-title":"Cytotoxic KLRG1+ IL-7R- effector CD8+ T cells distinguish kidney transplant recipients controlling cytomegalovirus reactivation","volume":"16","author":"Sun","year":"2025","journal-title":"Front Immunol"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.108078","article-title":"Landscape of exhausted virus-specific CD8 T cells in chronic LCMV infection","volume":"32","author":"Sandu","year":"2020","journal-title":"Cell Rep"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2023.1107511","article-title":"Single-cell RNA sequencing reveals in vivo osteoimmunology interactions between the immune and skeletal systems","volume":"14","author":"Wang","year":"2023","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-019-0312-6","article-title":"Subsets of exhausted CD8(+) T cells differentially mediate tumor control and respond to checkpoint blockade","volume":"20","author":"Miller","year":"2019","journal-title":"Nat Immunol"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14215183","article-title":"Heterogeneity and differentiation trajectories of infiltrating CD8+ T cells in lung adenocarcinoma","volume":"14","author":"Song","year":"2022","journal-title":"Cancers (Basel)"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2024.101489","article-title":"Multicellular ecotypes shape progression of lung adenocarcinoma from ground-glass opacity toward advanced stages","volume":"5","author":"Deng","year":"2024","journal-title":"Cell Rep Med"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.1186\/s12979-025-00550-8","article-title":"CD8+ T cell heterogeneity in aging: Insights from single-cell profiling","volume":"23","author":"Filippov","year":"2025","journal-title":"Immun Ageing"},{"key":"B94","doi-asserted-by":"publisher","first-page":"5128","DOI":"10.1038\/s41467-022-32869-x","article-title":"Heterogeneity and transcriptome changes of human CD8(+) T cells across nine decades of life","volume":"13","author":"Lu","year":"2022","journal-title":"Nat Commun"},{"key":"B95","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1038\/s41590-023-01720-w","article-title":"The transcriptional cofactor Tle3 reciprocally controls effector and central memory CD8(+) T cell fates","volume":"25","author":"Zhao","year":"2024","journal-title":"Nat Immunol"},{"key":"B96","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1111\/IMR.13057","article-title":"Epigenetics and CD8(+) T cell memory","volume":"305","author":"Montacchiesi","year":"2022","journal-title":"Immunol Rev"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.2139\/ssrn.3919725","article-title":"Silicon-based biomaterials modulate the adaptive immune response of T lymphocytes to promote osteogenesis\/angiogenesis via epigenetic regulation","volume":"12","author":"Xia","year":"2023","journal-title":"Adv Healthc Mater"},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.1172\/jci133473","article-title":"Parathyroid hormone-dependent bone formation requires butyrate production by intestinal microbiota","volume":"130","author":"Li","year":"2020","journal-title":"J Clin Invest"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.738762","article-title":"New insights on CD8(+) T cells in inflammatory bowel disease and therapeutic approaches","volume":"12","author":"Casalegno Gardu\u00f1o","year":"2021","journal-title":"Front Immunol"},{"key":"B100","doi-asserted-by":"publisher","DOI":"10.5217\/ir.2024.00185","article-title":"Gut, bone, and muscle: The triad of osteosarcopenia in inflammatory bowel disease","volume":"23","author":"Sharma","year":"2025","journal-title":"Intest Res"},{"key":"B101","doi-asserted-by":"publisher","DOI":"10.1155\/2021\/6643808","article-title":"Tissue-resident memory-like CD8(+) T cells exhibit heterogeneous characteristics in tuberculous pleural effusion","volume":"2021","author":"Yu","year":"2021","journal-title":"J Immunol Res"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-024-01462-3","article-title":"Trafficking circuit of CD8(+) T cells between the intestine and bone marrow governs antitumour immunity","volume":"26","author":"Shi","year":"2024","journal-title":"Nat Cell Biol"},{"key":"B103","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a041829","article-title":"Effector functions of conventional and unconventional Mycobacterium tuberculosis (Mtb)-specific T cells","volume":"16","author":"Panda","year":"2026","journal-title":"Cold Spring Harb Perspect Med"},{"key":"B104","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.cir-21-0588","article-title":"Holistic characterization of tumor monocyte-to-macrophage differentiation integrates distinct immune phenotypes in kidney cancer","volume":"10","author":"Mujal","year":"2022","journal-title":"Cancer Immunol Res"},{"key":"B105","doi-asserted-by":"publisher","DOI":"10.7150\/thno.40663","article-title":"CD8(+) T-cell plasticity regulates vascular regeneration in type-2 diabetes","volume":"10","author":"Liang","year":"2020","journal-title":"Theranostics"},{"key":"B106","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1128423","article-title":"A theoretical framework of immune cell phenotypic classification and discovery","volume":"14","author":"Hu","year":"2023","journal-title":"Front Immunol"},{"key":"B107","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxac038","article-title":"CD8 T-cell heterogeneity during T-cell exhaustion and PD-1-targeted immunotherapy","volume":"34","author":"Ando","year":"2022","journal-title":"Int Immunol"},{"key":"B108","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2506168123","article-title":"Functionally heterogeneous intratumoral CD4(+)CD8(+) double-positive T cells can give rise to single-positive T cells","volume":"123","author":"Li","year":"2026","journal-title":"Proc Natl Acad Sci USA"},{"key":"B109","doi-asserted-by":"publisher","DOI":"10.3390\/v14091906","article-title":"Heterogenous CD8+ T cell maturation and 'polarization' in acute and convalescent COVID-19 patients","volume":"14","author":"Kudryavtsev","year":"2022","journal-title":"Viruses"},{"key":"B110","doi-asserted-by":"publisher","DOI":"10.1186\/s13040-025-00427-y","article-title":"Immune cell profiles and predictive modeling in osteoporotic vertebral fractures using XGBoost machine learning algorithms","volume":"18","author":"Chen","year":"2025","journal-title":"Biodata Min"},{"key":"B111","doi-asserted-by":"publisher","first-page":"152779","DOI":"10.1016\/J.AAanT.2025.152779","article-title":"The bone-immune interface shapes skeletal regeneration","volume":"265","author":"Gei\u00dfler","year":"2026","journal-title":"Ann Anat"},{"key":"B112","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1268078","article-title":"CD8 T cell response and its released cytokine IFN-\u03b3 are necessary for lung alveolar epithelial repair during bacterial pneumonia","volume":"14","author":"Zhang","year":"2023","journal-title":"Front Immunol"},{"key":"B113","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1038\/s42003-023-04975-z","article-title":"Elevated glutamate impedes anti-HIV-1 CD8\u2009+\u2009T cell responses in HIV-1-infected individuals on antiretroviral therapy","volume":"6","author":"Wang","year":"2023","journal-title":"Commun Biol"},{"key":"B114","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202503095","article-title":"Mitochondrial regulation of CD8+ T cells: Mechanisms and therapeutic modulation","volume":"12","author":"Chen","year":"2025","journal-title":"Adv Sci (Weinh)"},{"key":"B115","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-024-01923-9","article-title":"NaCl enhances CD8(+) T\u2009cell effector functions in cancer immunotherapy","volume":"25","author":"Scirgolea","year":"2024","journal-title":"Nat Immunol"},{"key":"B116","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1016\/j.cmet.2023.01.009","article-title":"Sodium perturbs mitochondrial respiration and induces dysfunctional Tregs","volume":"35","author":"C\u00f4rte-Real","year":"2023","journal-title":"Cell Metab"},{"key":"B117","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2025.1729997","article-title":"The critical role of inflammation in osteoporosis prediction unveiled by a machine learning framework integrating multi-source data","volume":"16","author":"Liu","year":"2025","journal-title":"Front Physiol"},{"key":"B118","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00036.2016","article-title":"Osteoimmunology: The conceptual framework unifying the immune and skeletal systems","volume":"97","author":"Okamoto","year":"2017","journal-title":"Physiol Rev"},{"key":"B119","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2012.167","article-title":"New developments in osteoimmunology","volume":"8","author":"Takayanagi","year":"2012","journal-title":"Nat Rev Rheumatol"},{"key":"B120","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0038199","article-title":"Osteoclast activated FoxP3+ CD8+ T-cells suppress bone resorption in vitro","volume":"7","author":"Buchwald","year":"2012","journal-title":"PLoS One"},{"key":"B121","doi-asserted-by":"publisher","DOI":"10.1177\/0192623317735316","article-title":"Bone and the immune system","volume":"45","author":"Weitzmann","year":"2017","journal-title":"Toxicol Pathol"},{"key":"B122","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2022.116468","article-title":"Rheumatoid arthritis and osteoimmunology: The adverse impact of a deregulated immune system on bone metabolism","volume":"162","author":"Andreev","year":"2022","journal-title":"Bone"},{"key":"B123","doi-asserted-by":"publisher","DOI":"10.1007\/s11914-024-00874-2","article-title":"Interplay between skeletal and hematopoietic cells in the bone marrow microenvironment in homeostasis and aging","volume":"22","author":"Quarato","year":"2024","journal-title":"Curr Osteoporos Rep"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1874242\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T04:46:50Z","timestamp":1781239610000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1874242\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,12]]},"references-count":123,"alternative-id":["10.3389\/fimmu.2026.1874242"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1874242","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,12]]},"article-number":"1874242"}}