{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T21:54:14Z","timestamp":1789163654373,"version":"build-2803163510"},"reference-count":29,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,6,10]],"date-time":"2022-06-10T00:00:00Z","timestamp":1654819200000},"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:p>Lower extremity arteriosclerosis obliterans (LEASO) is a vascular disease that may result in adult limb loss worldwide. CD4<jats:sup>+<\/jats:sup>T cell-mediated immunity plays a significant role in LEASO. The T cell immunoglobulin and mucin domain 3 (Tim-3) and inhibitory receptor programmed cell death-1 (PD-1) are well-known immune checkpoints that play crucial roles in regulating CD4<jats:sup>+<\/jats:sup>T cell activation or tolerance. In this study, blood mononuclear cells were isolated from the blood samples of healthy controls and patients who were diagnosed with LEASO for the first time [stage III or IV according to the Fontaine classification system and had not received drugs (except for heparin) or surgery treatment]. We concluded the higher proportion of Tim-3<jats:sup>+<\/jats:sup>PD-1<jats:sup>+<\/jats:sup>CD4<jats:sup>+<\/jats:sup>T cells in human higher stage LEASO, and oxidized low-density lipoprotein increased Tim-3 and PD-1 co-expression by activating CD4<jats:sup>+<\/jats:sup>T cells in a dose- dependent manner. Tim-3<jats:sup>+<\/jats:sup>PD-1<jats:sup>+<\/jats:sup>CD4<jats:sup>+<\/jats:sup>T cells displayed a more active status and produced more anti-atherogenic cytokines compared to Tim-3<jats:sup>-<\/jats:sup>PD-1<jats:sup>-<\/jats:sup>CD4<jats:sup>+<\/jats:sup>T cells. Apart from the increased frequency, the altered function of Tim-3<jats:sup>+<\/jats:sup>PD-1<jats:sup>+<\/jats:sup>CD4<jats:sup>+<\/jats:sup>T cells was also observed in LEASO compared to those from healthy controls. These <jats:italic>in vitro<\/jats:italic> results indicated that Tim-3 and PD-1 might be promising early warning targets of higher stage LEASO. In addition, the blockade of Tim-3 and PD-1 signaling pathways aggravated the pro-atherogenic Th1 responses in LEASO, further suggesting that the cardiovascular safety must be a criterion considered in using immune checkpoint inhibitors to reverse T cell exhaustion during tumors and chronic viral infections.<\/jats:p>","DOI":"10.3389\/fimmu.2022.871362","type":"journal-article","created":{"date-parts":[[2022,6,10]],"date-time":"2022-06-10T12:59:09Z","timestamp":1654865949000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Increased Level of Tim-3+PD-1+CD4+T Cells With Altered Function Might Be Associated With Lower Extremity Arteriosclerosis 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