Gender and the Connection between Distress Tolerance and Psychopathology

This study investigated the potential moderating role gender plays in the association of distress tolerance (DT) with internalizing and externalizing symptoms of psychopathology. I hypothesized that DT would have a main effect on resilience to both internalizing and externalizing problems. Further, I expected that gender would moderate this effect for externalizing, but not internalizing, symptoms, such that men would exhibit a stronger (inverse) relationship between DT and externalizing problems. I tested these hypotheses in samples of 1,211 undergraduates and 224 treatment-seeking adults. There was strong evidence for the main effect of DT on both symptom dimensions, but the data did not support the gender moderation hypothesis. I recommend that future research replicates these analyses in larger clinical samples with more diverse forms of psychopathology

CD4+ cytolytic effectors are inefficient in the clearance of Listeria monocytogenes

Cytotoxic T lymphocytes (CTL) recognize and lyse target cells through the interaction of the T-cell receptor complex with the class I or class II major histocompatibility complex (MHC). The production of class I-restricted CTL has been shown to be critical to the elimination of specific pathogens including . However, the function of class II-restricted CTL in the clearance of intracellular pathogens is poorly understood. H-2β-microglobulin-deficient mice (βM−/−) are not able to produce CD8 CTL in response to infection with . We used this model to evaluate the efficacy of class II-restricted CTL, in the absence of a class I-restricted response, during a primary infection with . We demonstrate that, despite their effectiveness in adoptive transfer of protection, -specific CD4 class II-restricted cytotoxic lymphocytes are ineffective in decreasing titres of in the spleen after an established infection. In βM−/− mice, persistence of in the spleen was found preferentially in class II-negative cells. Surprisingly, class I-restricted CTL from C57BL/6 mice were capable of decreasing bacterial titres during an established infection even in the absence of detectable class I on the surface of cells from βM−/− mice. These data strongly suggest that, in the absence of a class I-restricted response, pathogens that elicit a class II-restricted cytotoxic response may escape prompt eradication by the immune system

Genomic Analysis of Immune Cell Infiltrates Across 11 Tumor Types

Background: Immune infiltration of the tumor microenvironment has been associated with improved survival for some patients with solid tumors. The precise makeup and prognostic relevance of immune infiltrates across a broad spectrum of tumors remain unclear

Anti-PD-1 Checkpoint Therapy Can Promote the Function and Survival of Regulatory T Cells

We have previously shown in a model of claudin-low breast cancer that regulatory T cells (Tregs) are increased in the tumor microenvironment (TME) and express high levels of PD-1. In mouse models and patients with triple-negative breast cancer, it is postulated that one cause for the lack of activity of anti-PD-1 therapy is the activation of PD-1-expressing Tregs in the TME. We hypothesized that the expression of PD-1 on Tregs would lead to enhanced suppressive function of Tregs and worsen antitumor immunity during PD-1 blockade. To evaluate this, we isolated Tregs from claudin-low tumors and functionally evaluated them ex vivo. We compared transcriptional profiles of Tregs isolated from tumor-bearing mice with or without anti-PD-1 therapy using RNA sequencing. We found several genes associated with survival and proliferation pathways; for example, Jun, Fos, and Bcl2 were significantly upregulated in Tregs exposed to anti-PD-1 treatment. Based on these data, we hypothesized that anti-PD-1 treatment on Tregs results in a prosurvival phenotype. Indeed, Tregs exposed to PD-1 blockade had significantly higher levels of Bcl-2 expression, and this led to increased protection from glucocorticoid-induced apoptosis. In addition, we found in vitro and in vivo that Tregs in the presence of anti-PD-1 proliferated more than control Tregs. PD-1 blockade significantly increased the suppressive activity of Tregs at biologically relevant Treg/Tnaive cell ratios. Altogether, we show that this immunotherapy blockade increases proliferation, protection from apoptosis, and suppressive capabilities of Tregs, thus leading to enhanced immunosuppression in the TME

Assembly-based inference of B-cell receptor repertoires from short read RNA sequencing data with V'DJer

Motivation: B-cell receptor (BCR) repertoire profiling is an important tool for understanding the biology of diverse immunologic processes. Current methods for analyzing adaptive immune receptor repertoires depend upon PCR amplification of VDJ rearrangements followed by long read amplicon sequencing spanning the VDJ junctions. While this approach has proven to be effective, it is frequently not feasible due to cost or limited sample material. Additionally, there are many existing datasets where short-read RNA sequencing data are available but PCR amplified BCR data are not. Results: We present here V'DJer, an assembly-based method that reconstructs adaptive immune receptor repertoires from short-read RNA sequencing data. This method captures expressed BCR loci from a standard RNA-seq assay. We applied this method to 473 Melanoma samples from The Cancer Genome Atlas and demonstrate V'DJer's ability to accurately reconstruct BCR repertoires from short read mRNA-seq data

A colitogenic memory CD4+ T cell population mediates gastrointestinal graft-versus-host disease

Damage to the gastrointestinal tract is a major cause of morbidity and mortality in graft-versus-host disease (GVHD) and is attributable to T cell–mediated inflammation. In this work, we identified a unique CD4+ T cell population that constitutively expresses the β2 integrin CD11c and displays a biased central memory phenotype and memory T cell transcriptional profile, innate-like properties, and increased expression of the gut-homing molecules α4β7 and CCR9. Using several complementary murine GVHD models, we determined that adoptive transfer and early accumulation of β2 integrin–expressing CD4+ T cells in the gastrointestinal tract initiated Th1-mediated proinflammatory cytokine production, augmented pathological damage in the colon, and increased mortality. The pathogenic effect of this CD4+ T cell population critically depended on coexpression of the IL-23 receptor, which was required for maximal inflammatory effects. Non–Foxp3-expressing CD4+ T cells produced IL-10, which regulated colonic inflammation and attenuated lethality in the absence of functional CD4+Foxp3+ T cells. Thus, the coordinate expression of CD11c and the IL-23 receptor defines an IL-10–regulated, colitogenic memory CD4+ T cell subset that is poised to initiate inflammation when there is loss of tolerance and breakdown of mucosal barriers

Machine-learning prediction of tumor antigen immunogenicity in the selection of therapeutic epitopes

Current tumor neoantigen calling algorithms primarily rely on epitope/major histocompatibility complex (MHC) binding affinity predictions to rank and select for potential epitope targets. These algorithms do not predict for epitope immunogenicity using approaches modeled from tumor-specific antigen data. Here, we describe peptide-intrinsic biochemical features associated with neoantigen and minor histocompatibility mismatch antigen immunogenicity and present a gradient boosting algorithm for predicting tumor antigen immunogenicity. This algorithm was validated in two murine tumor models and demonstrated the capacity to select for therapeutically active antigens. Immune correlates of neoantigen immunogenicity were studied in a pan-cancer data set from The Cancer Genome Atlas and demonstrated an association between expression of immunogenic neoantigens and immunity in colon and lung adenocarcinomas. Lastly, we present evidence for expression of an out-of-frame neoantigen that was capable of driving antitumor cytotoxic T-cell responses. With the growing clinical importance of tumor vaccine therapies, our approach may allow for better selection of therapeutically relevant tumor-specific antigens, including nonclas-sic out-of-frame antigens capable of driving antitumor immunity