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

BACKGROUND: 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. METHODS: 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 CD8(hi) T cells, as well as CD3-negative CD8(lo) lymphocytes as an approximate subset of NK cells. In addition, expression of TLR2, TLR4, IL1RL1, and TRAILR on CD14(+) monocytes were investigated. RESULTS: Prior to ART, TB-IRIS patients had higher percentages of CD8(hi) 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(+)CD8(hi) T cells remained higher in TB-IRIS patients after 3 months of ART (p≤0.013). Though these patterns were less pronounced in CD3(-)CD8(lo) 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. CONCLUSION: TB-IRIS is preceded by a high level of exhausted (KLRG1(+)PD-1(+)) CD8(hi) 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.