Tuberculosis-Associated Immune Restoration Syndrome in HIV-1-Infected Patients Involves Tuberculin-Specific CD4 Th1 Cells and KIR-Negative γδ T Cells

Abstract

Tuberculosis (TB)-associated immune restoration syndrome (IRS) is a frequent event (10 to 30%) in HIV-1-infected patients receiving antiretroviral treatment and is associated with an increased number of IFN-γ-producing tuberculin-specific cells. To further understand the immune mechanisms of TB-IRS and to identify predictive factors, we prospectively analyzed the Th1 and TCRγδ T cells known to be involved in mycobacterial defenses and dendritic cells at baseline and after antiretroviral and TB treatment in 24 HIV-1+ patients, 11 with and 13 without IRS. At baseline, these two groups differed by significantly lower proportions of TCRγδ and Vδ2+ T cells displaying the inhibitory receptors CD94/NKG2 and CD158ah,b in IRS patients. The two groups did not differ in the baseline characteristics of CD8 or CD4 T cells or TLR-2 expression on monocytes or myeloid/plasmacytoid dendritic cells. During IRS, the increase in tuberculin-specific IFN-γ-producing cells involved only highly activated effector memory multifunctional (IFN-γ+TNF-α+IL-2−) CD4 T cells, whereas activated HLA-DR+ CD4+ T cells also increased during IRS. In contrast, dendritic cells decreased significantly during IRS and there were no changes in TLR-2 expression. Finally, the Vδ2+ T cells, mostly killer Ig-related receptor (KIR) (CD94/NKG2− and CD158−), significantly peaked during IRS but not in non-IRS patients. In conclusion, IRS is associated with an increase in the number of activated tuberculin-specific effector memory CD4 T cells and of KIR−Vδ2+ TCRγδ+ T cells. Higher proportions of Vδ2+TCRγδ+ T cells lacking KIR expression are present as baseline and distinguish patients who will develop IRS from those who will not.