NKT Cell Responses Research Articles

Impaired Proliferative Response of Vα24 NKT Cells from Cancer Patients Against α-Galactosylceramide

Human invariant V alpha 24(+) NKT cells are a relatively new subpopulation of lymphocytes. It has been reported that V alpha 24 NKT cells are significantly involved in some human diseases. We have evaluated the number and function of V alpha 24 NKT cells in both healthy volunteers and cancer patients. In this study we found that V alpha 24 NKT cells in unfractionated PBMCs obtained from cancer patients did not respond efficiently to alpha-galactosylceramide (alpha-GalCer) in vitro. Thus, their proportion after stimulation with alpha-GalCer was smaller than that found in healthy volunteers. However, the cancer patients' V alpha 24 NKT cells retained cytotoxic activity against malignant target cells, and they could efficiently proliferate to alpha-GalCer when fractionated by sorting. Furthermore, we found that addition of G-CSF to the culture could restore the low proliferative response of V alpha 24 NKT cells from cancer patients. These results suggest that some functions of NKT cells in cancer patients are impaired, and this observation carries significant implications for immunotherapy-based cancer treatments.

Activating immunity in the liver. II. IFN-beta attenuates NK cell-dependent liver injury triggered by liver NKT cell activation.

Dendritic cell (DC)-dependent activation of liver NKT cells triggered by a single i.v. injection of a low dose (10-100 ng/mouse) of alpha-galactosyl ceramide (alphaGalCer) into mice induces liver injury. This response is particularly evident in HBs-tg B6 mice that express a transgene-encoded hepatitis B surface Ag in the liver. Liver injury following alphaGalCer injection is suppressed in mice depleted of NK cells, indicating that NK cells play a role in NK T cell-initiated liver injury. In vitro, liver NKT cells provide a CD80/86-dependent signal to alphaGalCer-pulsed liver DC to release IL-12 p70 that stimulates the IFN-gamma response of NKT and NK cells. Adoptive transfer of NKT cell-activated liver DC into the liver of nontreated, normal (immunocompetent), or immunodeficient (RAG(-/-) or HBs-tg/RAG(-/-)) hosts via the portal vein elicited IFN-gamma responses of liver NK cells in situ. IFN-beta down-regulates the pathogenic IL-12/IFN-gamma cytokine cascade triggered by NKT cell/DC/NK cell interactions in the liver. Pretreating liver DC in vitro with IFN-beta suppressed their IL-12 (but not IL-10) release in response to CD40 ligation or specific (alphaGalCer-dependent) interaction with liver NKT cells and down-regulated the IFN-gamma response of the specifically activated liver NKT cells. In vivo, IFN-beta attenuated the NKT cell-triggered induction of liver immunopathology. This study identifies interacting subsets of the hepatic innate immune system (and cytokines that up- and down-regulate these interactions) activated early in immune-mediated liver pathology.

During Trypanosoma cruzi infection CD1d-restricted NK T cells limit parasitemia and augment the antibody response to a glycophosphoinositol-modified surface protein.

Trypanosoma cruzi is a protozoan parasite that chronically infects many mammalian species and in humans causes Chagas' disease, a chronic inflammatory disease. The parasite expresses glycophosphoinositol (GPI), which potently stimulates interleukin 12 (IL-12) production. During T. cruzi infection IL-12, and possibly GPI, might stimulate NK T cells to affect the protective and chronic inflammatory responses. Here we report that during T. cruzi infection CD1d-restricted NK T cells are stimulated as NK T-cell-deficient mice have greater parasitemia. Furthermore, during T. cruzi infection the percentages of NK T cells in the liver and spleen become decreased for prolonged periods of time, and in vitro stimulation of NK T cells derived from livers of chronically infected mice, compared to uninfected mice, results in increased gamma interferon and IL-4 secretion. Moreover, in NK T-cell-deficient mice the chronic-phase antibody response to a GPI-modified surface protein is decreased. These results indicate that, during the acute infection, NK T cells limit parasitemia and that, during the chronic phase, NK T cells augment the antibody response. Thus, during T. cruzi infection the quality of an individual's NK T-cell response can affect the level of parasitemia and parasite tissue burden, the intensity of the chronic inflammatory responses, and possibly the outcome of Chagas' disease.

Unique sensitivity to α-galactosylceramide of NKT cells in the uterus

It was previously reported that NKT cells, which are mainly present in the liver of mice, are also present in the uterus and that these uterine NKT cells are associated with abortion under overactivated conditions. In this study, we further examined their phenotypic and functional properties. In parallel with the progression of pregnancy, the number of uterine lymphocytes increased. This increase accompanied an increase in the number of TCRαβ + T cells and NKT cells in the uterus, although the number of NKT cells decreased at late pregnancy. Approximately one-third of the TCRαβ + cells were NKT cells at the early pregnant stage, while this ratio decreased toward late pregnancy. These uterine NKT cells were found to respond to α-galactosylceramide (α-GalCer) differently in comparison with liver NKT cells. In contrast to the apoptotic response of liver NKT cells on day 1 after α-GalCer injection, uterine NKT cells expanded prominently without such apoptosis. The majority of liver NKT cells were CD4 +. In contrast, almost all of the uterine NKT cells were double negative CD4 −8 −. However, similar to liver NKT cells, uterine NKT cells used an invariant chain of Vα14Jα281 gene for TCRα. The resistance against apoptosis might be due to the high expression of bcl-2 on uterine NKT cells after α-GalCer activation. Other evidence was that macrophages which existed in the pregnant uterus carried an activation marker, CD69, and could potentially produce many cytokines by their activation. The present results suggest that uterine NKT cells and surrounding macrophages are quite different in function from those in the liver.

Different Influence of Macrophage Migration Inhibitory Factor (MIF) in Signal Transduction Pathway of Various T Cell Subsets

It has been shown that macrophage migration inhibitory factor (MIF) modulates not only macrophage functions, but also T cell functions. However, detailed analysis of the MIF function on responses of various T cell subpopulations remained to be elucidated. In this report, using a neutralizing anti-MIF monoclonal antibody (mAb) we examined MIF functions on various T cell lineages. It was shown that anti-MIF mAb inhibited antigen-specific responses of both IFN-γ producing and IL-4 producing T cells. The inhibition appeared to be related to blockade of the signal pathway via T cell receptor (TCR) but not that via IL-2 receptor (IL-2R). However, the anti-MIF mAb showed no inhibitory effect on NK-T cell responses stimulated through TCR. These results suggest that MIF is involved in the signal pathway via TCR in mainstream T cells but not in NK-T cells.

Murine natural killer T(NKT) cells [correction of natural killer cells] contribute to the granulomatous reaction caused by mycobacterial cell walls.

Mice injected with deproteinized cell walls prepared from the strain H37rv of Mycobacterium tuberculosis develop a granuloma-like lesion in which NKT cells are predominant. NKT cells play a primary role in the granulomatous response, because the latter does not occur in Jalpha281(-/-) mice, which miss NKT cells. The glycolipidic fraction of the cell walls is responsible for the recruitment of NKT cells; the recruiting activity is associated with fractions containing phosphatidylinositolmannosides. These results define a powerful experimental set up for studying the in vivo induction of NKT cell responses to microbial components.