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Here, we demonstrate that congenital ALV-J infection induces the production of high-frequency and activated CD4<jats:sup>+<\/jats:sup>CD25<jats:sup>+<\/jats:sup>Tregs that maintain persistent immunotolerance. A model of congenital infection by ALV-J was established in fertilized eggs, and hatched chicks showed persistent immunotolerance characterized by persistent viremia, immune organ dysplasia, severe imbalance of the ratio of CD4<jats:sup>+<\/jats:sup>\/CD8<jats:sup>+<\/jats:sup>T cells in blood and immune organs, and significant decrease in CD3<jats:sup>+<\/jats:sup>T cells and Bu-1<jats:sup>+<\/jats:sup>B cells in the spleen. Concurrently, the mRNA levels of IL-2, IL-10, and IFN-\u03b3 showed significant fluctuations in immune organs. Moreover, the frequency of CD4<jats:sup>+<\/jats:sup>CD25<jats:sup>+<\/jats:sup>Tregs in blood and immune organs significantly increased, and the frequency of CD4<jats:sup>+<\/jats:sup>CD25<jats:sup>+<\/jats:sup>Tregs was positively correlated with changes in ALV-J load in immune organs. Interestingly, CD4<jats:sup>+<\/jats:sup>CD25<jats:sup>+<\/jats:sup>Tregs increased in the marginal zone of splenic nodules in ALV-J-infected chickens and dispersed to the germinal center. In addition, the proliferation and activation of B cells in splenic nodules was inhibited, and the number of IgM<jats:sup>+<\/jats:sup>and IgG<jats:sup>+<\/jats:sup>cells in the marginal zone significantly decreased. We further found that the mRNA levels of TGF- \u03b2 and CTLA-4 in CD4<jats:sup>+<\/jats:sup>CD25<jats:sup>+<\/jats:sup>Tregs of ALV-J-infected chickens significantly increased. Together, high-frequency and activated CD4<jats:sup>+<\/jats:sup>CD25<jats:sup>+<\/jats:sup>Tregs inhibited B cells functions by expressing the inhibitory cytokine TGF-\u03b2 and inhibitory surface receptor CTLA-4, thereby maintaining persistent immunotolerance in congenital ALV-J-infected chickens.<\/jats:p>","DOI":"10.1186\/s13567-021-00989-9","type":"journal-article","created":{"date-parts":[[2021,9,15]],"date-time":"2021-09-15T11:03:31Z","timestamp":1631703811000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["High-frequency and activation of CD4+CD25+ T cells maintain persistent immunotolerance induced by congenital ALV-J infection"],"prefix":"10.1186","volume":"52","author":[{"given":"Shuhai","family":"He","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaoying","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Defang","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianguo","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4323-2541","authenticated-orcid":false,"given":"Ziqiang","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,9,15]]},"reference":[{"key":"989_CR1","first-page":"1167","volume":"6","author":"LN Payne","year":"1992","unstructured":"Payne LN, Gillespie AM, Howes K (1992) Myeloid leukaemogenicity and transmission of the HPRS-103 strain of avian leukosis virus. 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