CD1d-restricted NKT cells: an interstrain comparison

CD1d-restricted Va14-Ja281 invariant abTCR1 (NKT) cells are well defined in the C57BL/6 mouse strain, but they remain poorly characterized in non-NK1.1-expressing strains. Surrogate markers for NKT cells such as abTCR1CD42CD82 and DX51CD31 have been used in many studies, although their effectiveness in defining this lineage remains to be verified. Here, we compare NKT cells among C57BL/6, NK1.1-congenic BALB/c, and NK1.1-congenic nonobese diabetic mice. NKT cells were identified and compared using a range of approaches: NK1.1 expression, surrogate phenotypes used in previous studies, labeling with CD1d/a-galactosylceramide tetramers, and cytokine production. Our results demonstrate that NKT cells and their CD4/CD8-defined subsets are present in all three strains, and confirm that nonobese diabetic mice have a numerical and functional deficiency in these cells. We also highlight the hazards of using surrogate phenotypes, none of which accurately identify NKT cells,and one in particular (DX51CD31) actually excludes these cells. Finally, our results support the concept that NK1.1 expression may not be an ideal marker for CD1d-restricted NKT cells, many of which are NK1.1-negative, especially within the CD41 subset and particularly in NK1.1-congenic BALB/c mice

Innate immunity defines the capacity of antiviral T cells to limit persistent infection

Effective immunity requires the coordinated activation of innate and adaptive immune responses. Natural killer (NK) cells are central innate immune effectors, but can also affect the generation of acquired immune responses to viruses and malignancies. How NK cells influence the efficacy of adaptive immunity, however, is poorly understood. Here, we show that NK cells negatively regulate the duration and effectiveness of virus-specific CD4+ and CD8+ T cell responses by limiting exposure of T cells to infected antigen-presenting cells. This impacts the quality of T cell responses and the ability to limit viral persistence. Our studies provide unexpected insights into novel interplays between innate and adaptive immune effectors, and define the critical requirements for efficient control of viral persistence

Cyclophosphamide Chemotherapy Sensitizes Tumor Cells to TRAIL-Dependent CD8 T Cell-Mediated Immune Attack Resulting in Suppression of Tumor Growth

Background: Anti-cancer chemotherapy can be simultaneously lymphodepleting and immunostimulatory. Pre-clinical models clearly demonstrate that chemotherapy can synergize with immunotherapy, raising the question how the immune system can be mobilized to generate anti-tumor immune responses in the context of chemotherapy. Methods and Findings: We used a mouse model of malignant mesothelioma, AB1-HA, to investigate T cell-dependent tumor resolution after chemotherapy. Established AB1-HA tumors were cured by a single dose of cyclophosphamide in a CD8 T cell- and NK cell-dependent manner. This treatment was associated with an IFN-α/β response and a profound negative impact on the anti-tumor and total CD8 T cell responses. Despite this negative effect, CD8 T cells were essential for curative responses. The important effector molecules used by the anti-tumor immune response included IFN-γ and TRAIL. The importance of TRAIL was supported by experiments in nude mice where the lack of functional T cells could be compensated by agonistic anti-TRAIL-receptor (DR5) antibodies. Conclusion: The data support a model in which chemotherapy sensitizes tumor cells for T cell-, and possibly NK cell-, mediated apoptosis. A key role of tumor cell sensitization to immune attack is supported by the role of TRAIL in tumor resolution and explains the paradox of successful CD8 T cell-dependent anti-tumor responses in the absence of CD8 T cell expansion

Evidence for Type Ia Supernova Diversity from Ultraviolet Observations with the Hubble Space Telescope

We present ultraviolet (UV) spectroscopy and photometry of four Type Ia supernovae (SNe 2004dt, 2004ef, 2005M, and 2005cf) obtained with the UV prism of the Advanced Camera for Surveys on the Hubble Space Telescope. This dataset provides unique spectral time series down to 2000 Angstrom. Significant diversity is seen in the near maximum-light spectra (~ 2000--3500 Angstrom) for this small sample. The corresponding photometric data, together with archival data from Swift Ultraviolet/Optical Telescope observations, provide further evidence of increased dispersion in the UV emission with respect to the optical. The peak luminosities measured in uvw1/F250W are found to correlate with the B-band light-curve shape parameter dm15(B), but with much larger scatter relative to the correlation in the broad-band B band (e.g., ~0.4 mag versus ~0.2 mag for those with 0.8 < dm15 < 1.7 mag). SN 2004dt is found as an outlier of this correlation (at > 3 sigma), being brighter than normal SNe Ia such as SN 2005cf by ~0.9 mag and ~2.0 mag in the uvw1/F250W and uvm2/F220W filters, respectively. We show that different progenitor metallicity or line-expansion velocities alone cannot explain such a large discrepancy. Viewing-angle effects, such as due to an asymmetric explosion, may have a significant influence on the flux emitted in the UV region. Detailed modeling is needed to disentangle and quantify the above effects.Comment: 17 pages, 13 figures, accepted by Ap