{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T06:15:33Z","timestamp":1783664133828,"version":"3.55.0"},"reference-count":71,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T00:00:00Z","timestamp":1783641600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100014718","name":"Innovative Research Group Project of the National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100014718","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Dysregulated immune responses and extensive inflammatory damage to several organs are hallmarks of systemic lupus erythematosus (SLE), a highly heterogeneous systemic autoimmune disease that significantly impairs patients\u2019 quality of life and prognosis. Persistent antigenic stimulation causes T cell exhaustion (Tex), a unique functional state that is carefully controlled by exogenous, temporal, and spatial factors. Tex plays a special bidirectional regulatory role in SLE: on the one hand, it exerts a protective effect by suppressing the excessive activation of autoreactive T cells, thereby mitigating immune-mediated damage to target organs; on the other hand, abnormal exhaustion of specific T cell subsets leads to a loss of immunoregulatory function and may even promote the secretion of pro-inflammatory cytokines, thereby exacerbating pathological damage. Therapeutic strategies based on this dual mechanism focus on restoring immune homeostasis by enhancing protective exhaustion and inhibiting pathogenic exhaustion processes; this can be achieved through precise regulation of exhausted T cell subsets, improvement of the immune microenvironment, and interventions targeting key signalling pathways. This article provides a systematic review of the core molecular mechanisms and phenotypic characteristics of Tex, highlighting the latest research advances regarding its bidirectional regulatory role in SLE, and discusses in detail relevant diagnostic biomarkers and potential targeted therapeutic strategies. It aims to provide new insights and a theoretical basis for the clinical assessment, personalised treatment, and targeted drug development of SLE.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1871551","type":"journal-article","created":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T05:38:09Z","timestamp":1783661889000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["T cell exhaustion: a two-sided blade in systemic lupus erythematosus, from molecular mechanisms to clinical translation"],"prefix":"10.3389","volume":"17","author":[{"given":"Yanwei","family":"Bi","sequence":"first","affiliation":[{"name":"Department of Pediatrics, The Second Xiangya Hospital of Central South University","place":["Changsha, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feifeng","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The Second Xiangya Hospital of Central South 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