Date Published: April 25, 2019
Publisher: Public Library of Science
Author(s): Odin Goovaerts, Marguerite Massinga-Loembé, Pascale Ondoa, Ann Ceulemans, William Worodria, Harriet Mayanja-Kizza, Robert Colebunders, Luc Kestens, Esaki M. Shankar.
Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an inflammatory complication in HIV-TB co-infected patients receiving antiretroviral therapy (ART). The exact contribution of T cells, natural killer (NK) cells, and monocytes to TB-IRIS development remains unclear. Here, we studied the expression of exhaustion markers on lymphocytes at different intervals during ART.
We compared 13 HIV-TB patients who developed TB-IRIS with 13 patients who did not (HIV+TB+), 13 HIV-patients without TB (HIV+TB-) and 9 HIV/TB-negative controls (HIV-TB-). Patients did not differ in age, gender, or CD4-count prior to ART. Frozen peripheral blood mononuclear cells, collected before ART and during 3 months and 9 months of ART, were analysed using flow cytometry. We examined expression of KLRG1, PD-1 and IL-27R on CD4+ and CD8hi T cells, as well as CD3-negative CD8lo lymphocytes as an approximate subset of NK cells. In addition, expression of TLR2, TLR4, IL1RL1, and TRAILR on CD14+ monocytes were investigated.
Prior to ART, TB-IRIS patients had higher percentages of CD8hi T cells that are KLRG1+PD-1+ compared to each control group (p≤0.034). Though PD-1 expression decreased during ART in all groups (p≤0.026), the percentage KLRG1+PD-1+CD8hi T cells remained higher in TB-IRIS patients after 3 months of ART (p≤0.013). Though these patterns were less pronounced in CD3-CD8lo lymphocytes, the percentage of KLRG1+ cells was higher in TB-IRIS patients prior to ART (p≤0.043). In contrast, no clear differences could be observed for CD4+ T cells or monocytes.
TB-IRIS is preceded by a high level of exhausted (KLRG1+PD-1+) CD8hi T cells, which persists during 3 months of ART. This trait is potentially mirrored in a subpopulation of NK cells, but not CD4+ T cells. Since a dysfunctional CD8+ lymphocyte compartment could predispose patients to TB-IRIS, the functional role of these cells prior to TB-IRIS development should be further explored.
During successful antiretroviral therapy (ART), a subgroup of HIV patients with a tuberculosis (TB) co-infection are at risk of developing a complication called paradoxical TB-associated immune reconstitution inflammatory syndrome (TB-IRIS) . TB-IRIS is characterized by worsening symptoms of TB, despite an effective initial response to concurrent TB-treatment . Marked by tissue-destructive inflammation and a wide array of symptoms, patients often require additional therapy which increases the cost of patient care . Moreover, diagnosis of TB-IRIS still mainly relies on clinical examinations and is often difficult to distinguish from other complications. Thus, there is an urgent need for reliable laboratory markers to predict this syndrome, since the immune-pathogenesis of TB-IRIS is still not well understood .
Decades of research into TB-IRIS have highlighted potential roles of the innate and the adaptive immune system in the inflammatory cascade that characterizes the disease [11,12,16,17]. Nonetheless, the pre-ART mechanisms that predispose the immune system to hyper-react upon ART initiation remain unclear. Despite being a well-documented risk factor, low pre-ART CD4 counts alone cannot account for all TB-IRIS cases. Since up to 25% of HIV-TB patients with severe immunosuppression develop TB-IRIS , other antecedent factors have to be at play in order for this complication to occur. We hypothesised that higher levels of T cell exhaustion prior to ART would predispose HIV-TB patients to develop TB-IRIS. Here, we describe higher levels of exhaustion in CD8hi T cells and a subpopulation of NK cells, but not CD4+ T cells, which precede and persist after TB-IRIS. In severely immunocompromised individuals, the functionality of these cells may thus be an additional determining factor in TB-IRIS development.