{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T10:30:50Z","timestamp":1790937050242,"version":"4.1.0"},"reference-count":24,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,10,7]],"date-time":"2021-10-07T00:00:00Z","timestamp":1633564800000},"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>Most persons living with HIV (PLWH) experience a significant restoration of their immunity associated with successful inhibition of viral replication after antiretroviral therapy (ART) initiation. Nevertheless, with the robust quantitative and qualitative restoration of CD4<jats:sup>+<\/jats:sup> T-lymphocytes, a fraction of patients co-infected with tuberculosis develop immune reconstitution inflammatory syndrome (TB-IRIS), a dysregulated inflammatory response that can be associated with significant tissue damage. Several studies underscored the role of adaptive immune cells in IRIS pathogenesis, but to what degree T lymphocyte activation contributes to TB-IRIS development remains largely elusive. Here, we sought to dissect the phenotypic landscape of T lymphocyte activation in PLWH coinfected with TB inititating ART, focusing on characterization of the profiles linked to development of TB-IRIS. We confirmed previous observations demonstrating that TB-IRIS individuals display pronounced CD4<jats:sup>+<\/jats:sup> lymphopenia prior to ART initiation. Additionally, we found an ART-induced increase in T lymphocyte activation, proliferation and cytotoxicity among TB-IRIS patients. Importantly, we demonstrate that TB-IRIS subjects display higher frequencies of cytotoxic CD8<jats:sup>+<\/jats:sup> T lymphocytes which is not affected by ART. Moreover, These patients exhibit higher levels of activated (HLA-DR<jats:sup>+<\/jats:sup>) and profilerative (Ki-67<jats:sup>+<\/jats:sup>) CD4<jats:sup>+<\/jats:sup> T cells after ART commencenment than their Non-IRIS counterparts. Our network analysis reveal significant negative correlations between Total CD4<jats:sup>+<\/jats:sup> T cells counts and the frequencies of Cytotoxic CD8<jats:sup>+<\/jats:sup> T cells in our study population which could suggest the existance of compensatory mechanisms for Mtb-infected cells elimination in the face of severe CD4<jats:sup>+<\/jats:sup> T cell lymphopenia. We also investigated the correlation between T lymphocyte activation profiles and the abundance of several inflammatory molecules in plasma. We applied unsupervised machine learning techniques to predict and diagnose TB-IRIS before and during ART. Our analyses suggest that CD4<jats:sup>+<\/jats:sup> T cell activation markers are good TB-IRIS predictors, whereas the combination of CD4<jats:sup>+<\/jats:sup> and CD8<jats:sup>+<\/jats:sup> T cells markers are better at diagnosing TB-IRIS patients during IRIS events Overall, our findings contribute to a more refined understanding of immunological mechanisms in TB-IRIS pathogenesis that may assist in new diagnostic tools and more targeted patient management.<\/jats:p>","DOI":"10.3389\/fimmu.2021.757843","type":"journal-article","created":{"date-parts":[[2021,10,9]],"date-time":"2021-10-09T22:51:21Z","timestamp":1633819881000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["Dynamics of T-Lymphocyte Activation Related to Paradoxical Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome in Persons With Advanced HIV"],"prefix":"10.3389","volume":"12","author":[{"given":"Rafael","family":"Tib\u00farcio","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz","family":"Barreto-Duarte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gopolan","family":"Naredren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Artur\u00a0T.\u00a0L.","family":"Queiroz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Selvaraj","family":"Anbalagan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaustuv","family":"Nayak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narayanan","family":"Ravichandran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajasekaran","family":"Subramani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lis R. 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