Tuberculosis preventive therapy in postpartum women with HIV modifies M. tuberculosis-specific and nonspecific immune responses

Background Tuberculosis (TB) has significant morbidity in pregnant and postpartum women with HIV (pregnant and PPWWHIV). TB preventive therapy (TPT) is recommended in pregnant and PPWWHIV with documented or presumed latent TB infection (LTBI). TB-stimulated IFNγ release assay and skin test positivity decline after TPT, but the underlying mechanisms and relationship with TB-specific immunologic memory are incompletely understood. We investigated this aspect in PPWWHIV. Methods PPWWHIV with LTBI received isoniazid TPT between 12 and 40 weeks postpartum. Blood obtained at 12 and 44 weeks postpartum was used to compare functional and phenotypic characteristics of unstimulated and TB-stimulated CD4+ and CD8+ conventional T cells (Tconv); unconventional T cells, including γδ, iNKT, MR1+ and MR1- MAIT, and NKT; NK; and antigen presenting cells (APC) pre- and post-TPT. Results In 45 participants with medians of 477 CD4+ T cells/µL and <50 HIV RNA copies/mL of plasma on antiretroviral therapy, both Tconv and innate immune cells responded to TB antigenic stimulation in vitro with an increase in functional markers. TPT was associated with a pronounced decrease in the proportions of granzyme B-expressing Tconv and unconventional T cell subsets both in TB-stimulated and unstimulated conditions. TB-stimulated Th1- and Th17-like responses in unconventional T cells also decreased from pre- to post-TPT. TB-stimulated conventional and unconventional regulatory T cells mostly decreased after TPT with a few exceptions. Very few changes were observed in circulating or TB-stimulated APC in response to TPT. Conclusions TPT was associated with a significant decrease in TB-specific T cell responses, including Tconv but mostly unconventional T cells, suggesting an important role of unconventional T cell memory in the control of TB infection. The prominent decrease of granzyme B-expressing T cells in response to TPT highlighted the importance of granzyme B in the maintenance of LTBI.