Background:  TB-associated Immune Restoration Syndrome (TB-IRS) in HIV-1-infected patients receiving HAART is a frequent event (10 to 30%) and is associated to an increase in interferon-gamma (IFN-γ) -producing tuberculin-specific cells number. Our objective was to better understand the mechanisms of the TB-IRS pathology and define predictive factors.

Methods:  We prospectively analyzed before and after HAART onset the Th1 and γδ-T cells known to be involved in mycobacterial defences, as well as dendritic cells and monocytes in 11 IRS and 13 non-IRS TB/HIV⁺-co-infected patients. Phenotypic analysis including killer cell inhibitory receptor (KIR) and intracellular cytokine staining (ICS) studies were performed.

Results:  At baseline, IRS-to-be patients differed from non-IRS-to-be ones by higher proportions of Vδ2⁺ γδ-T cells (23 vs 12%, p <0.05) that displayed less frequently the natural killer (NK) receptors CD94, CD158a, and CD158b (p <0.05). The negative signalling of these receptors was confirmed by the stronger IFN-γ production after CD3 triggering in the CD94 or CD158 negative than positive γδ-T cells. In contrast, these patients did not differ at baseline for CD8 and CD4 T cell activation (HLA-DR) and differentiation (CD45RA, CD62L) markers, or for maturation/activation (CD83,CD86) of myeloid and plasmacytoid dendritic cells (DC) or for quantification of monocytes and Toll-like receptor-2 (TLR-2) expression. After HAART onset, effector memory (CD45RA^–CD27⁺ and ^–) Vδ2⁺γδ⁺ T cells increased significantly more in IRS patients (p <0.05) and those cells remained significantly less CD158b and CD94 positive (6 and 31%, respectively) than in non-IRS patients (p <0.001, general linear model). At time of IRS, the increase in tuberculin-specific IFN-γ producing cells involved mostly CD4 T cells which represented a median 73% of the IFN-γ⁺CD3⁺ T cells. These cells co-produced tumor necrosis factor-alpha (TNF-α), but not interleukin-2 (IL-2) and displayed an extremely homogeneous differentiation profile of activated (99% HLA-DR⁺) effector memory (84% CD45RA^–CD27^–) T cells. This was associated to an increase of HLA-DR⁺ CD8 and CD4 activated T cells in IRS patients. In contrast, peripheral DC numbers decreased from 0.64% to 0.2% (p <0.05), without change in TLR2 expression.

Conclusions:  In conclusion, TB-IRS is associated with an increase of activated tuberculin-specific effector-memory CD4 T cells and of Vδ2⁺KIR^–γδ⁺ T cells. This latter characteristic is already present at baseline and appears to distinguish patients who will develop IRS from those who will not.