Dysfunction of Natural Killer T Cells in Patients with Active Mycobacterium tuberculosis Infection

Abstract

d Natural killer T (NKT) cells are known to play a protective role in the immune responses of mice against a variety of infectious pathogens. However, little is known about the detailed information of NKT cells in patients with Mycobacterium tuberculosis infection. The aims of this study were to examine NKT cell levels and functions in patients with active M. tuberculosis infection, to investigate relationships between NKT cell levels and clinical parameters, and to determine the mechanism responsible for the poor response to ␣-galactosylceramide (␣-GalCer). NKT cell levels were significantly lower in the peripheral blood of pulmonary tuberculosis and extrapulmonary tuberculosis patients, and the proliferative responses of NKT cells to ␣-GalCer were also lower in patients, whereas NKT cell levels and responses were comparable in latent tuberculosis infection subjects and healthy controls. Furthermore, this NKT cell deficiency was found to be correlated with serum C-reactive protein levels. In addition, the poor response to ␣-GalCer in M. tuberculosis-infected patients was found to be due to increased NKT cell apoptosis, reduced CD1d expression, and a defect in NKT cells. Notably, M. tuberculosis infection was associated with an elevated expression of the inhibitory programmed death-1 (PD-1) receptor on NKT cells, and blockade of PD-1 signaling enhanced the response to ␣-GalCer. This study shows that NKT cell levels and functions are reduced in M. tuberculosis-infected patients and these deficiencies were found to reflect the presence of active tuberculosis.

Increased percentage of IFN-γ producing CD56+CD3+ cells in active tuberculosis patients upon CFP-10 stimulation of peripheral mononuclear cells

“…Barcelos et al [20] found that patients have a higher percentage of CD56 þ CD3 þ than infected controls, and Kulpraneet et al [19] showed that in PBMCs cultures stimulated with mycobacteria, TB patients had a greater percentage of IFN-g producing NKT cells compared to controls. In pulmonary and extrapulmonary TB patients, invariant NKT cells have a decreased proliferative capacity in response to a-GalCer, compared with latent infected individuals and healthy controls [38]. Our results also show that, regardless of BCG vaccination and antigen used (PPD or CFP-10), PTB and TSTþ HHC have a greater percentage of CD56 þ CD3 þ CD69 þ proliferating precursors and IFN-g producers compared to TSTÀ Non HHC, who showed a negligible responses.…”

Mucosal-Associated Invariant T Cell Deficiency in Systemic Lupus Erythematosus

“…In recent reports, PD-1 and its ligands have been implicated in the induction and maintenance of T cell and NKT cell anergy (37,38,42,43). In our previous report, we demonstrated that NKT cell dysfunction was associated with upregulation of inhibitory receptor PD-1 in active tuberculosis, and it was partially recovered by blockade of PD-1 (44). In this study, we investigated the relevance of PD-1 expression to MAIT cell dysfunction in SLE and RA.…”

Invariant Natural Killer T Cells: Boon or Bane in Immunity to Intracellular Bacterial Infections?

“…Alteration in the frequencies of iNKT cells has been reported in pulmonary tuberculosis patients. Using antibodies mainly against CD3 and the Vα24 and Vβ11 chains of iNKT cell TCR to identify iNKT cells, some studies have shown a numerical deficiency of iNKT cells in tuberculosis patients [43,44,45,46,47]. However, other studies contradict these findings and report a steady incline in the number of these cells in the peripheral blood [48,49,50,51].…”

“…In the case of Brucella suis infection, CD4+CD8- iNKT cells have been found to effectively inhibit bacterial growth and/or kill the bacteria through the production of IFN-γ and cytotoxic activities [55]. Recently, Kee et al [46 ]conducted a detailed analysis of iNKT cells in patients with active M. tuberculosis infection. They found that the number of these cells was lower in the peripheral blood of both pulmonary and extrapulmonary tuberculosis patients when compared to patients with latent tuberculosis and to healthy controls.…”

“…Furthermore, M. tuberculosis -infected patients show a reduced response to α-GalCer, found to be due to increased iNKT cell apoptosis and reduced CD1d expression. In addition, iNKT cells from tuberculosis patients show higher levels of the inhibitory programmed death-1 (PD-1) receptor, and the blocking of PD-1 signalling improves the response to α-GalCer [46]. Thus, iNKT cell levels and functions appear to be diminished in M. tuberculosis patients and these deficiencies reflect the presence of active tuberculosis.…”