A Study of T Cell Tolerance to the Tumor-Associated Antigen MDM2: Cytokines Can Restore Antigen Responsiveness, but Not High Avidity T Cell Function

BACKGROUND: Most tumor-associated antigens (TAA) currently used for immunotherapy of cancer are also expressed in normal tissues, which may induce tolerance and impair T cell-mediated immunity. However, there is limited information about how physiological expression in normal tissues alters the function of TAA-specific T cells. METHODOLOGY/PRINCIPAL FINDINGS: We used a T cell receptor transgenic model to study how MDM2 expression in normal tissues affects the function of T cells specific for this TAA that is found at high levels in many different types of tumors. We found that some MDM2-specific T cells escaped thymic deletion and persisted in the peripheral T cell pool. When stimulated with antigen, these T cells readily initiated cell division but failed to proliferate and expand, which was associated with a high rate of apoptosis. Both IL-2 and IL-15 efficiently rescued T cell survival and antigen-specific T cell proliferation, while IL-7 and IL-21 were ineffective. Antigen-stimulated T cells showed impaired expression of the effector molecules CD43, granzyme-B and IFN-γ, a defect that was completely restored when T cells were stimulated in the presence of IL-2. In contrast, IL-15 and IL-21 only restored the expression of CD43 and granzyme-B, but not IFN-γ production. Finally, peptide titration experiments with IL-2 rescued T cells indicated that they were of lower avidity than non-tolerant control T cells expressing the same TCR. CONCLUSIONS/SIGNIFICANCE: These data indicate that cytokines can rescue the antigen-specific proliferation and effector function of MDM2-specific T cells, although this does not lead to the recovery of high avidity T cell function. This study sheds light on possible limitations of immunotherapy approaches that target widely expressed TAA, such as MDM2

Chemical tagging with APOGEE: discovery of a large population of N-rich stars in the inner Galaxy

Formation of globular clusters (GCs), the Galactic bulge, or galaxy bulges in general is an important unsolved problem in Galactic astronomy. Homogeneous infrared observations of large samples of stars belonging to GCs and the Galactic bulge field are one of the best ways to study these problems. We report the discovery by APOGEE (Apache Point Observatory Galactic Evolution Experiment) of a population of field stars in the inner Galaxy with abundances of N, C, and Al that are typically found in GC stars. The newly discovered stars have high [N/Fe], which is correlated with [Al/Fe] and anticorrelated with [C/Fe]. They are homogeneously distributed across, and kinematically indistinguishable from, other field stars within the same volume. Their metallicity distribution is seemingly unimodal, peaking at [Fe/H] ∼ −1, thus being in disagreement with that of the Galactic GC system. Our results can be understood in terms of different scenarios. N-rich stars could be former members of dissolved GCs, in which case the mass in destroyed GCs exceeds that of the surviving GC system by a factor of ∼8. In that scenario, the total mass contained in so-called ‘first-generation’ stars cannot be larger than that in ‘second-generation’ stars by more than a factor of ∼9 and was certainly smaller. Conversely, our results may imply the absence of a mandatory genetic link between ‘second-generation’ stars and GCs. Last, but not least, N-rich stars could be the oldest stars in the Galaxy, the by-products of chemical enrichment by the first stellar generations formed in the heart of the Galaxy

The 13th Data Release of the Sloan Digital Sky Survey: First Spectroscopic Data from the SDSS-IV Survey Mapping Nearby Galaxies at Apache Point Observatory

The fourth generation of the Sloan Digital Sky Survey (SDSS-IV) began observations in July 2014. It pursues three core programs: APOGEE-2,MaNGA, and eBOSS. In addition, eBOSS contains two major subprograms: TDSS and SPIDERS. This paper describes the first data release from SDSS-IV, Data Release 13 (DR13), which contains new data, reanalysis of existing data sets and, like all SDSS data releases, is inclusive of previously released data. DR13 makes publicly available 1390 spatially resolved integral field unit observations of nearby galaxies from MaNGA,the first data released from this survey. It includes new observations from eBOSS, completing SEQUELS. In addition to targeting galaxies and quasars, SEQUELS also targeted variability-selected objects from TDSS and X-ray selected objects from SPIDERS. DR13 includes new reductions ofthe SDSS-III BOSS data, improving the spectrophotometric calibration and redshift classification. DR13 releases new reductions of the APOGEE-1data from SDSS-III, with abundances of elements not previously included and improved stellar parameters for dwarf stars and cooler stars. For the SDSS imaging data, DR13 provides new, more robust and precise photometric calibrations. Several value-added catalogs are being released in tandem with DR13, in particular target catalogs relevant for eBOSS, TDSS, and SPIDERS, and an updated red-clump catalog for APOGEE.This paper describes the location and format of the data now publicly available, as well as providing references to the important technical papers that describe the targeting, observing, and data reduction. The SDSS website, http://www.sdss.org, provides links to the data, tutorials and examples of data access, and extensive documentation of the reduction and analysis procedures. DR13 is the first of a scheduled set that will contain new data and analyses from the planned ~6-year operations of SDSS-IV.PostprintPeer reviewe

Hantaviral mechanisms driving HLA class I antigen presentation require both RIG-I and TRIF

Stemcel biology/Regenerative medicine (incl. bloodtransfusion

Deletion is neither sufficient nor necessary for the induction of peripheral tolerance in mature CD8(+) T cells

Previous reports have demonstrated clonal deletion of CD8(+) T cells during peripheral tolerance induction to tissue antigens. However, direct evidence demonstrating a causal connection between deletion and tolerance has not been reported because of model limitations in which the tissue antigens were expressed in vital organs. Thus, studies were initiated in a mouse model where expression of a membrane-bound ovalbumin fusion protein (mOVA) was driven by a prostate specific androgen regulated probasin promotor, providing restricted expression in a non-vital organ where antigen levels can be abrogated through androgen deprivation. Adoptive transfer of mOVA specific CD8(+) T cells (OT-I) was used to assess the development of peripheral tolerance. Proliferation of OT-I cells was observed, as was partial deletion of transferred OT-I cells. Although deletion occurred, the long-term persistence of a stable level of OT-I cells was observed. Importantly, the persistent OT-I cells lost antigen responsiveness within 3 weeks of transfer. Castration resulted in loss of high-level prostate mOVA expression, with a resultant abrogation of tolerance induction, but surprisingly did not affect the deletion rate of OT-I cells. In contrast, abrogation of deletion through the adoptive transfer of OT-I cells from third generation CD95-deficient mice had no effect on tolerance induction. These data demonstrate the necessity for continued expression of tissue antigen throughout the establishment of peripheral tolerance. Furthermore, these findings demonstrate that deletion is neither sufficient nor required for CD8(+) T-cell tolerance to tissue antigens, suggesting that regulatory events independent of deletion are necessary for peripheral tolerance induction to prostate antigens

A blood-borne antigen induces rapid T–B cell contact: a potential mechanism for tolerance induction

Understanding the difference between the development of a productive T-cell response and tolerance is central to discerning how the immune system functions. Intravenous injection of soluble protein is thought to mimic the presentation of self-serum and orally introduced antigens. It is generally toleragenic. The current view is that this outcome reflects the failure of ‘immunogenic’ dendritic cells to relocate to the T-cell zone of the secondary lymphoid tissues. Here, using a peptide/I-E(k) tetramer and antibodies to stain splenic sections, we showed that antigen-specific T cells were activated in the spleen within hours of injection or feeding of protein. The activated T cells were found to be located at the T–B junction, the bridging zone and the B-cell area, interacting directly with B cells. In addition, B cells gain the ability to present antigen. Our results suggest a way for T cells to be stimulated by blood-borne antigen presented by naïve B cells, a potential mechanism of tolerance induction