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While most transplantation rejections occur due to the adaptive immune response, the proinflammatory response of innate immunity is necessary for the activation of adaptive immunity. Botryllus schlosseri, a colonial tunicate, which is the nearest invertebrate group to the vertebrates, is devoid of T- and B-cell-based adaptive immunity. It has unique characteristics that make it a valuable model system for studying innate immunity mechanisms: (i) a natural allogeneic transplantation phenomenon that results in either fusion or rejection; (ii) whole animal regeneration and noninflammatory resorption on a weekly basis; (iii) allogeneic resorption which is comparable to human chronic rejection. Recent studies in B. schlosseri have led to the recognition of a molecular and cellular framework underlying the innate immunity loss of tolerance to allogeneic tissues. Additionally, B. schlosseri was developed as a model for studying hematopoietic stem cell (HSC) transplantation, and it provides further insights into the similarities between the HSC niches of human and B. schlosseri. In this review, we discuss why studying the molecular and cellular pathways that direct successful innate immune tolerance in B. schlosseri can provide novel insights into and potential modulations of these immune processes in humans.<\/jats:p>","DOI":"10.3390\/md19080454","type":"journal-article","created":{"date-parts":[[2021,8,9]],"date-time":"2021-08-09T05:17:06Z","timestamp":1628486226000},"page":"454","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Botryllus schlosseri as a Unique Colonial Chordate Model for the Study and Modulation of Innate Immune Activity"],"prefix":"10.3390","volume":"19","author":[{"given":"Oron","family":"Goldstein","sequence":"first","affiliation":[{"name":"Regenerative Medicine and Stem Cell Research Center, The Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edna Ayerim","family":"Mandujano-Tinoco","sequence":"additional","affiliation":[{"name":"Regenerative Medicine and Stem Cell Research Center, The Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva 8410501, Israel"},{"name":"Laboratory of Connective Tissue, Centro Nacional de Investigaci\u00f3n y Atenci\u00f3n de Quemados, Instituto Nacional de Rehabilitaci\u00f3n \u201cLuis Guillermo Ibarra Ibarra\u201d, Calzada Mexico-Xochimilco No. 289, Col. Arenal de Guadalupe, Tlalpan, Mexico City 14389, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1484-0310","authenticated-orcid":false,"given":"Tom","family":"Levy","sequence":"additional","affiliation":[{"name":"Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Hopkins Marine Station, Stanford University, Chan Zuckerberg Biohub, Pacific Grove, CA 93950, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shani","family":"Talice","sequence":"additional","affiliation":[{"name":"Regenerative Medicine and Stem Cell Research Center, The Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tal","family":"Raveh","sequence":"additional","affiliation":[{"name":"Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Hopkins Marine Station, Stanford University, Chan Zuckerberg Biohub, Pacific Grove, CA 93950, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orly","family":"Gershoni-Yahalom","sequence":"additional","affiliation":[{"name":"Regenerative Medicine and Stem Cell Research Center, The Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayelet","family":"Voskoboynik","sequence":"additional","affiliation":[{"name":"Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Hopkins Marine Station, Stanford University, Chan Zuckerberg Biohub, Pacific Grove, CA 93950, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3974-3296","authenticated-orcid":false,"given":"Benyamin","family":"Rosental","sequence":"additional","affiliation":[{"name":"Regenerative Medicine and Stem Cell Research Center, The Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1111\/imr.12153","article-title":"Innate allorecognition","volume":"258","author":"Oberbarnscheidt","year":"2014","journal-title":"Immunol. 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