Preventing tumor escape by targeting a post-proteasomal trimming independent epitope

Adoptive T cell therapy (ATT) can achieve regression of large tumors in mice and humans; however, tumors frequently recur. High target peptide-major histocompatibility complex-I (pMHC) affinity and T cell receptor (TCR)-pMHC affinity are thought to be critical to preventing relapse. Here, we show that targeting two epitopes of the same antigen in the same cancer cells via monospecific T cells, which have similar pMHC and pMHC-TCR affinity, results in eradication of large, established tumors when targeting the apparently subdominant but not the dominant epitope. Only the escape but not the rejection epitope required postproteasomal trimming, which was regulated by IFN-gamma, allowing IFN-gamma-unresponsive cancer variants to evade. The data describe a novel immune escape mechanism and better define suitable target epitopes for ATT

Flux Phase as a Dynamic Jahn-Teller Phase: Berryonic Matter in the Cuprates?

There is considerable evidence for some form of charge ordering on the hole-doped stripes in the cuprates, mainly associated with the low-temperature tetragonal phase, but with some evidence for either charge density waves or a flux phase, which is a form of dynamic charge-density wave. These three states form a pseudospin triplet, demonstrating a close connection with the E X e dynamic Jahn-Teller effect, suggesting that the cuprates constitute a form of Berryonic matter. This in turn suggests a new model for the dynamic Jahn-Teller effect as a form of flux phase. A simple model of the Cu-O bond stretching phonons allows an estimate of electron-phonon coupling for these modes, explaining why the half breathing mode softens so much more than the full oxygen breathing mode. The anomalous properties of $O^{2-}$ provide a coupling (correlated hopping) which acts to stabilize density wave phases.Comment: Major Revisions: includes comparisons with specific cuprate phonon modes, 16 eps figures, revte

Increased estrogen to androgen ratio enhances immunoglobulin levels and impairs B cell function in male mice

Sex steroids, such as estrogens and androgens, are important regulators of the humoral immune response. Studies in female mice have demonstrated that alteration of circulating estrogen concentration regulates antibody-mediated immunity. As males have normally little endogenous estrogen, we hypothesized that in males high estrogens and low androgens affect the immune system and enhance the allergic inflammatory response. Here, we studied transgenic male mice expressing human aromatase (AROM+). These animals have a high circulating estrogen to androgen ratio (E/A), causing female traits such as gynecomastia. We found that AROM+ male mice had significantly higher plasma immunoglobulin levels, particularly IgE. Flow cytometry analyses of splenocytes revealed changes in mature/immature B cell ratio together with a transcriptional upregulation of the Igh locus. Furthermore, higher proliferation rate and increased IgE synthesis after IgE class-switching was found. Subsequently, we utilized an ovalbumin airway challenge model to test the allergic response in AROM+ male mice. In line with above observations, an increase in IgE levels was measured, albeit no impact on immune cell infiltration into the lungs was detected. Together, our findings suggest that high circulating E/A in males significantly alters B cell function without any significant enhancement in allergic inflammation.</p

Managing tight-binding receptors for new separations technologies. 1998 annual progress report

'Whereas such traditional separation methodologies as ion exchange and solvent extraction require rapid interaction between ligands and metal ions, the most strongly binding ligands invariably bind slowly; e.g., cryptates bind and dissociate more slowly than macrocycles, which are slower than open-chain chelating ligands. This project seeks to maximize the binding and dissociation rates for tight-binding receptors in order to make them more useful to separations science. An alternative slow-binding technology is also under exploration.

Whole-body anatomy of human T cells.

Knowledge of the regional tissue distribution of T&nbsp;cell subsets is a prerequisite for understanding protective immunity and the pathophysiology of T&nbsp;cell-mediated diseases. In this issue of Immunity, Sathaliyawala et&nbsp;al. (2012) present a comprehensive human tissue T&nbsp;cell analysis

Adoptive immunotherapy: New assay for the identification of T cells with optimal avidity.

T cells expressing high avidity T-cell receptors (TCRs) have been shown to mediate superior therapeutic effects. A novel koff-rate assay allows for the quantitative and reproducible assessment of the avidity of TCRs for their ligands directly on living T cells, ex vivo. This assay might facilitate the selection of T cells with an optimal avidity for their target, hence favoring the development of adoptive immunotherapeutic regimens

CD8⁺ T cell differentiation in the aging immune system: Until the last clone standing.

A substantial deterioration of the na&iuml;ve CD8(+) T cell pool occurs regularly in humans beyond the age of 65 years. While recall responses to pathogens encountered during youth or adulthood are largely uncompromised, the de novo generation of memory responses by aged na&iuml;ve CD8(+) T cells is perturbed. In recent years evidence has accumulated that the diminished responsiveness of na&iuml;ve CD8(+) T cells in aged humans and other mammals coincides with a progressive loss of na&iuml;ve T cell receptor (TCR) repertoire diversity. In this review we focus on thymic involution and chronic latent viral infections as key factors driving the reduction in na&iuml;ve TCR repertoire diversity. We present novel insights gained by studying the antigen-driven differentiation of single CD8(+) T cells in young hosts and discuss possible implications of these insights for therapeutic support of the thinned-out clonal T cell repertoire of the elderly by vaccination or adoptive cell therapy

The smallest unit: Effector and memory CD8⁺ T cell differentiation on the single cell level.

CD8(+) T cell immune responses provide immediate protection against primary infection and durable memory capable of rapidly fighting off re-infection. Immediate protection and lasting memory are implemented by phenotypically and functionally distinct T cell subsets. While it is now widely accepted that these diverge from a common source of na&iuml;ve T cells (T(n)), the developmental relation and succession of effector and memory T cell subsets is still under intense debate. Recently, a distinct memory T cell subset has been suggested to possess stem cell-like features, sparking the hope to harness its capacity for self-renewal and diversification for successful therapy of chronic infections or malignant diseases. In this review we highlight current developmental models of memory generation, T cell subset diversification and T cell stemness. We discuss the importance of single cell monitoring techniques for adequately mapping these developmental processes and take a brief look at signaling components active in the putative stem cell-like memory T cell compartment