Increased KLRG1 and PD-1 expression on CD8 T lymphocytes in TB-IRIS.

Odin Goovaerts,Luc Kestens,Marguerite Massinga-Loembé,Robert Colebunders,Ann Ceulemans,Pascale Ondoa,Harriet Mayanja-Kizza,William Worodria,Esaki M Shankar

doi:10.1371/journal.pone.0215991

Abstract

BackgroundTuberculosis-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.MethodsWe 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.ResultsPrior 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.ConclusionTB-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.

Highlights

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) [1]
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 natural killer (NK) cells
Though PD-1 expression decreased during ART in all groups (p 0.026), the percentage KLRG1+PD-1+CD8hi T cells remained higher in Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) patients after 3 months of ART (p 0.013)

Summary

Introduction

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) [1]. Known risk factors of TB-IRIS include a high TB-antigen burden, a short interval between TB treatment and ART and, most importantly, a low CD4+ T cell count prior to ART initiation [7,8,9]. It should be noted, that not all HIV-TB patients under similar conditions of immunosuppression develop TB-IRIS. We studied the expression of exhaustion markers on lymphocytes at different intervals during ART.

Methods

Results

Conclusion