Dysfunction of natural killer T cells in patients with active Mycobacterium tuberculosis infection.
ABSTRACT 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 α-galactosylceramide (α-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 α-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 α-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 α-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.
Article: Individuals with pulmonary tuberculosis have lower levels of circulating CD1d-restricted NKT cells.[show abstract] [hide abstract]
ABSTRACT: Mycobacterium tuberculosis (MTB) is a leading cause of mortality worldwide from an infectious agent. Natural killer T (NKT) cells recognize mycobacterial antigens and contribute to anti-MTB immunity in mouse models. NKT cells were measured in subjects with pulmonary tuberculosis, MTB-exposed individuals, and healthy controls. NKT cell levels are selectively lower in peripheral blood mononuclear cells from individuals with pulmonary tuberculosis than in both MTB-exposed subjects and healthy control subjects. This apparent loss of NKT cells from the peripheral blood is sustained during the 6 months after the initiation of MTB treatment. These findings indicate that NKT cells may be an important component of antituberculosis immunity.The Journal of Infectious Diseases 05/2007; 195(9):1361-4. · 6.41 Impact Factor
Article: IFN-gamma acts directly on activated CD4+ T cells during mycobacterial infection to promote apoptosis by inducing components of the intracellular apoptosis machinery and by inducing extracellular proapoptotic signals.[show abstract] [hide abstract]
ABSTRACT: Despite many studies, the regulation of CD4(+) T cell apoptosis during the shutdown of immune responses is not fully understood. We have investigated the molecular mechanisms of IFN-gamma in regulating apoptosis of CD4(+) T cells during bacillus Calmette-Guérin (BCG) infection of mice. Our data provide new insight into the regulation of CD4(+) T cell apoptosis by IFN-gamma. As CD4(+) T cells responded to BCG infection, there was a coordinated increase in IFN-gamma production by effector CD4(+) T cells and a coordinated IFN-gamma-dependent up-regulation of many diverse apoptosis-pathway genes in effector CD4(+) T cells. Unexpectedly, IFN-gamma up-regulated transcripts and protein expression of Bcl-2, Bax, Bim, Bid, Apaf-1, and caspase-9 in activated CD4(+) T cells--components of the apoptosis machinery that are involved in promoting mitochondrial damage-mediated apoptosis. Wild-type, but not IFN-gamma knockout, CD4(+) T cells underwent apoptosis that was associated with damaged mitochondrial membranes. IFN-gamma also up-regulated expression of cell-extrinsic signals of apoptosis, including TRAIL, DR5, and TNFR1. Cell-extrinsic apoptosis signals from TNF-alpha, TRAIL, and NO were capable of damaging the mitochondrial membranes in activated CD4(+) T cells. Moreover, activated CD4(+) T cells from BCG-infected DR5, TNFR1, and inducible NO synthase knockout mice had impaired caspase-9 activity, suggesting impaired mitochondria-pathway apoptosis. We propose that IFN-gamma promotes apoptosis of CD4(+) T cells during BCG infection as follows: 1) by sensitizing CD4(+) T cells to apoptosis by inducing intracellular apoptosis molecules and 2) by inducing cell-extrinsic apoptosis signals that kill CD4(+) effector T cells.The Journal of Immunology 08/2007; 179(2):939-49. · 5.79 Impact Factor
Article: Modulation of human Valpha24(+)Vbeta11(+) NKT cells by age, malignancy and conventional anticancer therapies.[show abstract] [hide abstract]
ABSTRACT: Immunotherapy strategies aimed at increasing human Valpha24(+)Vbeta11(+) natural killer T (NKT) cell numbers are currently a major focus. To provide further information towards the goal of NKT cell-based immunotherapy, we assessed the effects of age, cancer status and prior anticancer treatment on NKT cell numbers and their expansion capacity following alpha-galactosylceramide (alpha-GalCer) stimulation. The percentage and absolute number of peripheral blood NKT cells was assessed in 40 healthy donors and 109 solid cancer patients (colorectal (n=33), breast (n=10), melanoma (n=17), lung (n=8), renal cell carcinoma (n=10), other cancers (n=31)). Responsiveness to alpha-GalCer stimulation was also assessed in 28 of the cancer patients and 37 of the healthy donors. Natural killer T cell numbers were significantly reduced in melanoma and breast cancer patients. While NKT numbers decreased with age in healthy donors, NKT cells were decreased in these cancer subgroups despite age and sex adjustments. Prior radiation treatment was shown to contribute to the observed reduction in melanoma patients. Although cancer patient NKT cells were significantly less responsive to alpha-GalCer stimulation, they remained capable of substantial expansion. Natural killer T cells are therefore modulated by age, malignancy and prior anticancer treatment; however, cancer patient NKT cells remain capable of responding to alpha-GalCer-based immenotherapies.British Journal of Cancer 12/2004; 91(11):1880-6. · 5.04 Impact Factor