TB-IRIS After Initiation of Antiretroviral Therapy Is Associated With Expansion of Preexistent Th1 Responses Against Mycobacterium tuberculosis Antigens

Abstract

The role of T-cell responses against Mycobacterium tuberculosis antigens in tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is unclear. Peripheral blood mononuclear cells from 45 HIV patients with treated TB, of whom 12 developed TB-IRIS, were collected at weeks 0, 2, and 6 of antiretroviral therapy (ART). Production of interferon-gamma (IFN-γ) and interleukin-2 by T cells after stimulation with purified protein derivative (PPD) or early secretory antigenic target-6 (ESAT-6) and T-cell expressions of CCR5 and CXCR3 were assessed by flow cytometry. IFN-γ and CXCL10 were assayed by enzyme-linked immunosorbent assay. TB-IRIS patients had higher proportions of PPD- and ESAT-6-reactive IFN-γ⁺CD4⁺ and CD3⁺CD4⁻ T cells at weeks 0, 2, and 6. IFN-γ levels were also higher in peripheral blood mononuclear cell culture supernatants at all times with PPD but only at weeks 2 and 6 with ESAT-6. There were few differences for interleukin-2. CXCL10 levels in supernatants after PPD and ESAT-6 stimulation were only higher at week 6. CXCR3⁺/CCR5⁺CD4⁺ T cells were higher at week 2, and CCR5⁺CD4⁺ T cells were higher at week 6. TB-IRIS is associated with Th1 responses against M. tuberculosis antigens by CD4⁺ and CD3⁺CD4⁻ T cells that are present before ART and amplified afterward. It is unclear if these cause immunopathology or reflect a high pathogen load.