Lower Pre-Treatment T Cell Activation in Early- and Late-Onset Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome

Abstract

BackgroundTuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an inflammatory complication in HIV-TB co-infected patients receiving antiretroviral therapy (ART). The role of disturbed T cell reconstitution in TB-IRIS is not well understood. We investigated T cell activation and maturation profiles in patients who developed TB-IRIS at different intervals during ART.MethodsTwenty-two HIV-TB patients who developed early-onset TB-IRIS and 10 who developed late-onset TB-IRIS were matched for age, sex and CD4 count to equal numbers of HIV-TB patients who did not develop TB-IRIS. Flow cytometry analysis was performed on fresh blood, drawn before and after ART initiation and during TB-IRIS events. T cell activation and maturation was measured on CD4+ and CD8+ T cells using CD45RO, CD38, HLA-DR, CCR7 and CD27 antibodies.ResultsCD8+ T cell activation before ART was decreased in both early-onset (77% vs. 82%, p = 0.014) and late-onset (71% vs. 83%, p = 0.012) TB-IRIS patients compared to non-IRIS controls. After ART initiation, the observed differences in T cell activation disappeared. During late-onset, but not early-onset TB-IRIS, we observed a skewing from memory to terminal effector CD4+ and CD8+ T cell populations (p≤0.028).ConclusionOur data provide evidence of reduced CD8+ T cell activation before ART as a common predisposing factor of early- and late-onset TB-IRIS. The occurrence of TB-IRIS itself was not marked by an over-activated CD8+ T cell compartment. Late- but not early-onset TB-IRIS was characterized by a more terminally differentiated T cell phenotype.

Robust Reconstitution of Tuberculosis-Specific Polyfunctional CD4+T-Cell Responses and Rising Systemic Interleukin 6 in Paradoxical Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome

“…These findings are similar to several other investigations [14,16] and are generally consistent with our previous report documenting reduced pre-ART systemic inflammation in those who later developed TB-IRIS [15]. Furthermore, we found no enrichment in late differentiation stage CD4 + T-cells in TB-IRIS.…”

“…Immunologically, higher pre-ART levels of immune activation and rapid increases in tuberculosis-specific interferon gamma (IFN-γ)-producing cells after ART initiation in HIV-infected adults have been associated with development of TB-IRIS [7,[9][10][11][12]. However, in several recent studies, levels of pre-ART immune activation were actually lower in TB-IRIS patients vs controls [13][14][15], and multiple reports have indicated that patients without TB-IRIS may also have robust increases in levels of pathogen-specific immune responses on ART [16,17]. Existing data are therefore inconclusive about whether higher levels of pre-ART immune activation predispose to TB-IRIS and whether tuberculosis-specific T-cells are involved in TB-IRIS pathogenesis.…”

Clinical and genetic markers associated with tuberculosis, HIV-1 infection, and TB/HIV-immune reconstitution inflammatory syndrome outcomes

“…Moreover, clinical risk factors already known to be associated with IRIS pathogenesis are (a) low baseline CD4 + T-cell count (< 50-100 cells per mm 3 ) combined with a short time interval between the beginning of TB treatment and cART [38][39][40][41][42] and (b) dissemination of TB to extrapulmonary sites, possibly reflecting a high bacterial load [43,44]. Nevertheless, despite the few biomarker descriptions associated with IRIS, there is still no one capable of predicting IRIS development currently being used in the clinical practice.…”

HIV infection and immune activation

“…Interestingly, after ART treatment initiation, the CD4 T cell memory was skewed towards effector-memory phenotype [32]. In another study, it was postulated that low CD8+ T cell activation (HLA-DR+/CD38+) could be a predisposing factor of both early and late onset TB-IRIS events and that late but not early onset IRIS showed a shift from memory to effector CD8+ and CD4+ T cells after ART initiation [33]. Wilkinson KA et al, studied also the effector function of TB-specific CD4 T cells and demonstrated an increase in IFN-gamma response as well as in perforin 1 and granzyme B expression in heat-killed H37Rv stimulated human PBMCs from paradoxical TB-IRIS patients compared to HIV-TB co-infected non-IRIS patients [34] further highlighting the effector function of TB-specific cells.…”