Invariant Natural Killer T-cell Dynamics in Human Immunodeficiency Virus-associated Tuberculosis

Background. Tuberculosis (TB) is the leading cause of mortality and morbidity in people living with human immunodeficiency virus (HIV) infection (PLWH). 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. Methods. In a cross-sectional study of 101 PLWH and HIV-uninfected South African patients with active TB and controls, iNKT cells were enumerated using alpha-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. Results. 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(-) subset depleted and degranulated around the time of TB-IRIS onset. Conclusions. Reduced iNKT cell CD4(+) subsets as a result of HIV-1 infection may skew iNKT cell functionality toward cytotoxicity. Increased CD4(-) cytotoxic iNKT cells may contribute to immunopathology in TB-IRIS. iNKT cells were depleted in patients with advanced HIV infection, most significantly immunoregulatory CD4+ subsets. In patients with HIV-associated TB who developed TB-IRIS, iNKT cells were elevated with increased degranulation compared to non-IRIS patients, implicating iNKT cells in TB-IRIS immunopathology.