Disease-specific changes in gammadelta T cell repertoire and function in patients with pulmonary tuberculosis.

Abstract

Although gammadelta T cells are known to contain the highest frequency of mycobacteria-reactive cells in humans and numerous studies have suggested that they play an important role in the initial immune response to Mycobacterium tuberculosis (Mtb), very few studies have attempted to analyze these cells in patients with active pulmonary tuberculosis. The aim of the present study was therefore to evaluate the consequences of infection on the number and activity of mycobacteria-reactive gammadelta T cells. Three-color flow cytometric analysis of blood and bronchoalveolar lavage gammadelta T cells of patients diagnosed with active pulmonary tuberculosis showed that compared with normal healthy subjects and patients with the unrelated pulmonary granulomatous diseases sarcoidosis and berylliosis the size of the mycobacteria-reactive Vgamma9+/Vdelta2+ gammadelta T cell subset in both the blood and lung was dramatically reduced. In addition, the Vgamma9+/Vdelta2+ cells left intact in patients with tuberculosis were refractory to in vitro stimulation by Mtb Ags, which are potent stimuli for these cells in normal subjects. Our results demonstrate for the first time a strong correlation between the absence or loss of the major Vgamma9+/Vdelta2+ Mtb-reactive subset of gammadelta T cells and manifestations of disease, consistent with the hypothesis that these gammadelta T cells play a role in the protective immune response to Mtb infection.

Generation of Nitric Oxide by the Inducible Nitric Oxide Synthase Protects γδ T Cells fromMycobacterium tuberculosis-Induced Apoptosis

“…T lymphocytes undergo apoptosis after TCR engagement only when chronically activated (activation-dependent apoptosis, AICD) (39 -42). This feature well applies to ␥␦ cell apoptosis induced by mycobacterial Ags (26) and may justify the selective disappearance of ␥␦ T cells from long-lasting chronic tubercular lesions and from the bronchoalveolar lavages of chronically infected patients (9,43). Because AICD mostly, although possibly nonexclusively, depends on the interaction between CD95 and its ligand (39 -42), we verified at which level NO interfered with the CD95 pathway.…”

“…This effect involves the limitation of lesion size, possibly via control of polymorphonuclear leukocytes homing and functions at the infection site (4,7). Expansion of the ␥␦ cell compartment differs in healthy subjects or in infected patients: peripheral blood ␥␦ cells expand in healthy hospital workers after contact with tuberculosis patients, whereas a loss of V␥9/V␦2 ϩ T cells in the bronchoalveolar lavages correlates with the severity of active pulmonary tuberculosis (8,9).…”

Impact of BCG vaccination on the repertoire of human γδ T cell receptors

“…Silver ( 20 – 23 ) has done BAL samples in persons with LTBI and not seen many γδ T cells in BAL. However, an older report ( 24 ) studied both blood and BAL and found a striking absence of γδ T cells in both locations in patients with active TB disease, suggesting that the absence of γδ T cells during response to disease was associated with TB susceptibility. Also, it is possible that protective γδ T cells could be present in the lung parenchyma after BCG vaccination, and not in the alveolar spaces amenable to BAL sampling.…”

Analysis of the components of Mycobacterium tuberculosis heat-resistant antigen (Mtb-HAg) and its regulation of γδ T-cell function

“…IPP- or HMBPP-induced γδ T cells can readily produce the anti-tuberculosis cytokines IFN-γ and TNF-α, which are capable of inducing macrophage or monocyte activation and play important roles in the body's antitumour, anti-infection, immunomodulation, immunosurveillance, and maintenance of immune tolerance abilities [ 8 – 11 ]. Although CD4 + and CD8 + αβ T cells have been clearly demonstrated to play an important role in protective immunity against Mtb infection [ 12 , 13 ], several lines of evidence over the past few years [ 14 – 16 ], including previous work from our laboratory [ 17 , 18 ], suggest that γδ T cells may also play an important role in host immunity against Mtb infection.…”