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PLWH with TB disease are at risk of the paradoxical TB-associated immune reconstitution inflammatory syndrome (TB-IRIS) when they commence antiretroviral therapy. However, the pathophysiology is incompletely understood and specific therapy is lacking. We investigated the hypothesis that invariant natural killer T (iNKT) cells contribute to innate immune dysfunction associated with TB-IRIS.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>In a cross-sectional study of 101 PLWH and HIV-uninfected South African patients with active TB and controls, iNKT cells were enumerated using \u03b1-galactosylceramide-loaded CD1d tetramers and subsequently functionally characterized by flow cytometry. In a second study of 49 people with HIV type 1 (HIV-1) and active TB commencing antiretroviral therapy, iNKT cells in TB-IRIS patients and non-IRIS controls were compared longitudinally.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Circulating iNKT cells were reduced in HIV-1 infection, most significantly the CD4+ subset, which was inversely associated with HIV-1 viral load. iNKT cells in HIV-associated TB had increased surface CD107a expression, indicating cytotoxic degranulation. Relatively increased iNKT cell frequency in patients with HIV-1 infection and active TB was associated with development of TB-IRIS following antiretroviral therapy initiation. iNKT cells in TB-IRIS were CD4+CD8\u2013 subset depleted and degranulated around the time of TB-IRIS onset.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Reduced iNKT cell CD4+ subsets as a result of HIV-1 infection may skew iNKT cell functionality toward cytotoxicity. Increased CD4\u2013 cytotoxic iNKT cells may contribute to immunopathology in TB-IRIS.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cid\/ciz501","type":"journal-article","created":{"date-parts":[[2019,6,11]],"date-time":"2019-06-11T19:11:20Z","timestamp":1560280280000},"page":"1865-1874","source":"Crossref","is-referenced-by-count":13,"title":["Invariant Natural Killer T-cell Dynamics in Human Immunodeficiency Virus\u2013associated Tuberculosis"],"prefix":"10.1093","volume":"70","author":[{"given":"Naomi F","family":"Walker","sequence":"first","affiliation":[{"name":"Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, South Africa"},{"name":"Infectious Diseases and Immunity, and Imperial College Wellcome Trust Centre for Global Health, Imperial College London, United Kingdom"},{"name":"Department of Medicine, University of Cape Town, Observatory, South 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