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

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-gamma-producing tuberculin-specific cells. To further understand the immune mechanisms of TB-IRS and to identify predictive factors, we prospectively analyzed the Th1 and TCRgammadelta 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 TCRgammadelta and Vdelta2(+) 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-gamma-producing cells involved only highly activated effector memory multifunctional (IFN-gamma(+)TNF-alpha(+)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 Vdelta2(+) 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(-)Vdelta2(+) TCRgammadelta(+) T cells. Higher proportions of Vdelta2(+)TCRgammadelta(+) T cells lacking KIR expression are present as baseline and distinguish patients who will develop IRS from those who will not.