{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,12]],"date-time":"2026-07-12T03:13:14Z","timestamp":1783825994465,"version":"3.55.0"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T00:00:00Z","timestamp":1748995200000},"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><jats:title>Background<\/jats:title><jats:p>Vascularized Composite Allotransplantation (VCA) is an important therapeutic option for patients that incur debilitating injuries to the face or limbs. The complexity and immunogenicity of tissue types within VCA grafts pose unique challenges and necessitate the use of intensive immunosuppression; however, graft rejection remains a challenge in VCA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Deep proteomic profiling and high dimensional analysis with cytometry time of flight were used to define the cell types and effector mechanisms elicited by VCA in BALB\/c (H-2Kd) &amp;gt; C57BL\/6 (H-2Kb) limb recipients. Spleen and cervical draining lymph nodes were collected post-transplant days 1, 3, 5, and 7 (n =4\u20136 mice\/group\/day). We identified dynamic, coordinated signatures in T cell and monocyte populations associated with VCA allograft rejection.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In comparison to syngeneic transplant recipients, allogeneic recipients exhibited significant alterations in the immune cell populations within secondary lymphoid tissues. These changes included very early expansion of double-negative TCR\u03b2<jats:sup>-<\/jats:sup> T cells, including IL-17A-producing \u03b3\u03b4 T cells, and patrolling monocytes. Subsequently, CD8+CD62L+ T cells and CD8+ effector\/effector memory T cells (Teff\/Tem), Ly6C<jats:sup>hi<\/jats:sup>CCR2<jats:sup>hi<\/jats:sup>CX3CR1<jats:sup>low<\/jats:sup> classical monocytes, CD4+ Teff\/Tem, and CD8+CD25<jats:sup>hi<\/jats:sup>CCR7<jats:sup>low<\/jats:sup> Teff\/Tem were increased by day 5. CD8+CD25<jats:sup>hi<\/jats:sup>CCR7<jats:sup>low<\/jats:sup> Teff\/Tem with the highest expression of IFN-\u03b3, perforin, and granzyme B were enriched by day 7.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>High dimensional proteomic analysis reveals multiple innate and Teff\/Tem subsets in acute rejection following VCA. In particular, IL-17A-producing \u03b3\u03b4 T cells and classical monocytes may be particularly important in initiating the alloimmune response in VCA recipients.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1584916","type":"journal-article","created":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T04:15:04Z","timestamp":1749010504000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["IL-17A-producing \u03b3\u03b4 T cells and classical monocytes are associated with a rapid alloimmune response following vascularized composite allotransplantation in mice"],"prefix":"10.3389","volume":"16","author":[{"given":"Tetsuya","family":"Tajima","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenming","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuling","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Reitsma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James T.","family":"Harden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Fuentes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayaka","family":"Sonehara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos O.","family":"Esquivel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia M.","family":"Martinez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheri M.","family":"Krams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200008173430704","article-title":"Successful hand transplantation. One-year follow-up. Louisville Hand Transplant Team","volume":"343","author":"Jones","year":"2000","journal-title":"N Engl J Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa072828","article-title":"Outcomes 18 months after the first human partial face transplantation","volume":"357","author":"Dubernard","year":"2007","journal-title":"N Engl J Med"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1097\/TP.0b013e3181ff1472","article-title":"The international registry on hand and composite tissue transplantation","volume":"90","author":"Petruzzo","year":"2010","journal-title":"Transplantation"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1111\/ajt.15704","article-title":"Hand transplantation in the United States: A review of the Organ Procurement and Transplantation Network\/United Network for Organ Sharing Database","volume":"20","author":"Hein","year":"2020","journal-title":"Am J Transplant"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajt.2024.01.020","article-title":"OPTN\/SRTR 2022 annual data report: vascularized composite allograft","volume":"24","author":"Hernandez","year":"2024","journal-title":"Am J Transplant"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1001\/jamasurg.2024.3748","article-title":"An update on the survival of the first 50 face transplants worldwide","volume":"159","author":"Homsy","year":"2024","journal-title":"JAMA Surg"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1097\/SAP.0000000000003056","article-title":"Two decades of hand transplantation: A systematic review of outcomes","volume":"88","author":"Wells","year":"2022","journal-title":"Ann Plast Surg"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.108806","article-title":"High-resolution phenotyping of early acute rejection reveals a conserved alloimmune signature","volume":"34","author":"Harden","year":"2021","journal-title":"Cell Rep"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.transproceed.2020.10.039","article-title":"Establishment of heterotopic hind limb transplantation model in the mouse","volume":"53","author":"Wang","year":"2021","journal-title":"Transplant Proc"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2023.101147","article-title":"High-dimensional profiling of pediatric immune responses to solid organ transplantation","volume":"4","author":"Rao","year":"2023","journal-title":"Cell Rep Med"},{"key":"B11","doi-asserted-by":"publisher","first-page":"748","DOI":"10.12688\/f1000research.11622.3","article-title":"CyTOF workflow: differential discovery in high-throughput high-dimensional cytometry datasets","volume":"6","author":"Nowicka","year":"2017","journal-title":"F1000Res"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1186\/2050-7771-2-1","article-title":"Monocyte and macrophage differentiation: circulation inflammatory monocyte as biomarker for inflammatory diseases","volume":"2","author":"Yang","year":"2014","journal-title":"Biomark Res"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1128\/microbiolspec.MCHD-0033-2016","article-title":"Murine monocytes: origins, subsets, fates, and functions","volume":"4","author":"Mildner","year":"2016","journal-title":"Microbiol Spectr"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.112513","article-title":"Tissue-resident, extravascular Ly6c(-) monocytes are critical for inflammation in the synovium","volume":"42","author":"Montgomery","year":"2023","journal-title":"Cell Rep"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-018-0029-z","article-title":"IFNgamma: signalling, epigenetics and roles in immunity, metabolism, disease and cancer immunotherapy","volume":"18","author":"Ivashkiv","year":"2018","journal-title":"Nat Rev Immunol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-6143.2005.00995.x","article-title":"IFN-gamma, produced by NK cells that infiltrate liver allografts early after transplantation, links the innate and adaptive immune responses","volume":"5","author":"Obara","year":"2005","journal-title":"Am J Transplant"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1111\/ajt.13865","article-title":"Interferon gamma and contact-dependent cytotoxicity are each rate limiting for natural killer cell-mediated antibody-dependent chronic rejection","volume":"16","author":"Lin","year":"2016","journal-title":"Am J Transplant"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1002\/micr.20170","article-title":"Prolonged limb allograft survival with CD 40 costimulation blockade, T-cell depletion, and megadose donor bone-marrow transfusion","volume":"25","author":"Tung","year":"2005","journal-title":"Microsurgery"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-6143.2008.02419.x","article-title":"CD8+ T-Cell depletion and rapamycin synergize with combined coreceptor\/stimulation blockade to induce robust limb allograft tolerance in mice","volume":"8","author":"Li","year":"2008","journal-title":"Am J Transplant"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1097\/01.tp.0000290277.23186.ad","article-title":"Long-term limb allograft survival using a short course of anti-CD45RB monoclonal antibody, LF 15-0195, and rapamycin in a mouse model","volume":"84","author":"Zhong","year":"2007","journal-title":"Transplantation"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1910701116","article-title":"Treg-inducing microparticles promote donor-specific tolerance in experimental vascularized composite allotransplantation","volume":"116","author":"Fisher","year":"2019","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aax8429","article-title":"In situ recruitment of regulatory T cells promotes donor-specific tolerance in vascularized composite allotransplantation","volume":"6","author":"Fisher","year":"2020","journal-title":"Sci Adv"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2024.11679","article-title":"Uterus transplant in women with absolute uterine-factor infertility","volume":"332","author":"Testa","year":"2024","journal-title":"JAMA"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-020-00452-4","article-title":"gammadelta T cells in tissue physiology and surveillance","volume":"21","author":"Ribot","year":"2021","journal-title":"Nat Rev Immunol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3726","article-title":"IL-17(+) gammadelta T cells as kick-starters of inflammation","volume":"18","author":"Papotto","year":"2017","journal-title":"Nat Immunol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2017.03.043","article-title":"Vgamma4 gammadelta T cells provide an early source of IL-17A and accelerate skin graft rejection","volume":"137","author":"Li","year":"2017","journal-title":"J Invest Dermatol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/jid.2012.16","article-title":"gammadelta T cells augment rejection of skin grafts by enhancing cross-priming of CD8 T cells to skin-derived antigen","volume":"132","author":"Rahimpour","year":"2012","journal-title":"J Invest Dermatol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1038\/s41581-021-00466-8","article-title":"Unconventional T cells and kidney disease","volume":"17","author":"Kaminski","year":"2021","journal-title":"Nat Rev Nephrol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/s1074-7613(03)00174-2","article-title":"Blood monocytes consist of two principal subsets with distinct migratory properties","volume":"19","author":"Geissmann","year":"2003","journal-title":"Immunity"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.172.7.4410","article-title":"Subpopulations of mouse blood monocytes differ in maturation stage and inflammatory response","volume":"172","author":"Sunderkotter","year":"2004","journal-title":"J Immunol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2024.07.010","article-title":"Both classical and non-classical monocytes patrol glomerular capillaries and promote acute glomerular inflammation","volume":"195","author":"Tan","year":"2024","journal-title":"Am J Pathol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1126\/science.aac9407","article-title":"Patrolling monocytes control tumor metastasis to the lung","volume":"350","author":"Hanna","year":"2015","journal-title":"Science"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1606253113","article-title":"Patrolling monocytes promote intravascular neutrophil activation and glomerular injury in the acutely inflamed glomerulus","volume":"113","author":"Finsterbusch","year":"2016","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B34","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1038\/nrcardio.2009.228","article-title":"Monocytes in atherosclerosis: subsets and functions","volume":"7","author":"Woollard","year":"2010","journal-title":"Nat Rev Cardiol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.22.012703.104702","article-title":"Central memory and effector memory T cell subsets: function, generation, and maintenance","volume":"22","author":"Sallusto","year":"2004","journal-title":"Annu Rev Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1111\/ajt.14145","article-title":"Applying mass cytometry to the analysis of lymphoid populations in transplantation","volume":"17","author":"Krams","year":"2017","journal-title":"Am J Transplant"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1097\/TP.0000000000004925","article-title":"Application of mass cytometry platforms to solid organ transplantation","volume":"108","author":"Zhang","year":"2024","journal-title":"Transplantation"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3488","article-title":"Multiplexed ion beam imaging of human breast tumors","volume":"20","author":"Angelo","year":"2014","journal-title":"Nat Med"},{"key":"B39","doi-asserted-by":"publisher","first-page":"1373","DOI":"10.1016\/j.cell.2018.08.039","article-title":"A structured tumor-immune microenvironment in triple negative breast cancer revealed by multiplexed ion beam imaging","volume":"174","author":"Keren","year":"2018","journal-title":"Cell"},{"key":"B40","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1016\/j.jid.2020.12.008","article-title":"Research techniques made simple: use of imaging mass cytometry for dermatological research and clinical applications","volume":"141","author":"Veenstra","year":"2021","journal-title":"J Invest Dermatol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1584916\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T04:15:05Z","timestamp":1749010505000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1584916\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,4]]},"references-count":40,"alternative-id":["10.3389\/fimmu.2025.1584916"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1584916","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,4]]},"article-number":"1584916"}}