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The bacteria responsible for causing tuberculosis in mammals and zebrafish are shown to preferentially recruit and infect permissive macrophages while evading microbicidal ones. Mycobacterial interference in macrophage production At its initial infection site the tuberculosis pathogen infects macrophages, which transport the bacteria to deeper tissues. How the bacteria survive in these host cells is not clear. Here Lalita Ramakrishnan and colleagues show that Mycobacterium tuberculosis and its close pathogenic relative Mycobacterium marinum have evolved a strategy to avoid microbicidal macrophages while recruiting those permissive to their survival. This preferential recruitment is accomplished in a two-step process. First, the bacteria mask the PAMPs (pathogen-associated molecular patterns) recognized by microbicidal macrophages by the production of mycobacterial phthiocerol dimycoceroserate lipids. Second, they produce phenolic glycolipids that promote recruitment of permissive macrophages via a host chemokine receptor 2-mediated pathway. The evolutionary survival of Mycobacterium tuberculosis , the cause of human tuberculosis, depends on its ability to invade the host, replicate, and transmit infection. At its initial peripheral infection site in the distal lung airways, M. tuberculosis infects macrophages, which transport it to deeper tissues 1 . How mycobacteria survive in these broadly microbicidal cells is an important question. Here we show in mice and zebrafish that M. tuberculosis , and its close pathogenic relative Mycobacterium marinum , preferentially recruit and infect permissive macrophages while evading microbicidal ones. This immune evasion is accomplished by using cell-surface-associated phthiocerol dimycoceroserate (PDIM) lipids 2 to mask underlying pathogen-associated molecular patterns (PAMPs). In the absence of PDIM, these PAMPs signal a Toll-like receptor (TLR)-dependent recruitment of macrophages that produce microbicidal reactive nitrogen species. Concordantly, the related phenolic glycolipids (PGLs) 2 promote the recruitment of permissive macrophages through a host chemokine receptor 2 (CCR2)-mediated pathway. Thus, we have identified coordinated roles for PDIM, known to be essential for mycobacterial virulence 3 , and PGL, which (along with CCR2) is known to be associated with human tuberculosis 4 , 5 . Our findings also suggest an explanation for the longstanding observation that M. tuberculosis initiates infection in the relatively sterile environment of the lower respiratory tract, rather than in the upper respiratory tract, where resident microflora and inhaled environmental microbes may continually recruit microbicidal macrophages through TLR-dependent signalling.

BackgroundChimeric antigen receptor (CAR) T-cell therapies have demonstrated transformational outcomes in the treatment of B-cell malignancies, but their widespread use is hindered by technical and logistical challenges associated with ex vivo cell manufacturing. To overcome these challenges, we developed VivoVec, a lentiviral vector-based platform for in vivo engineering of T cells. UB-VV100, a VivoVec clinical candidate for the treatment of B-cell malignancies, displays an anti-CD3 single-chain variable fragment (scFv) on the surface and delivers a genetic payload that encodes a second-generation CD19-targeted CAR along with a rapamycin-activated cytokine receptor (RACR) system designed to overcome the need for lymphodepleting chemotherapy in supporting successful CAR T-cell expansion and persistence. In the presence of exogenous rapamycin, non-transduced immune cells are suppressed, while the RACR system in transduced cells converts rapamycin binding to an interleukin (IL)-2/IL-15 signal to promote proliferation.MethodsUB-VV100 was administered to peripheral blood mononuclear cells (PBMCs) from healthy donors and from patients with B-cell malignancy without additional stimulation. Cultures were assessed for CAR T-cell transduction and function. Biodistribution was evaluated in CD34-humanized mice and in canines. In vivo efficacy was evaluated against normal B cells in CD34-humanized mice and against systemic tumor xenografts in PBMC-humanized mice.ResultsIn vitro, administration of UB-VV100 resulted in dose-dependent and anti-CD3 scFv-dependent T-cell activation and CAR T-cell transduction. The resulting CAR T cells exhibited selective expansion in rapamycin and antigen-dependent activity against malignant B-cell targets. In humanized mouse and canine studies, UB-VV100 demonstrated a favorable biodistribution profile, with transduction events limited to the immune compartment after intranodal or intraperitoneal administration. Administration of UB-VV100 to humanized mice engrafted with B-cell tumors resulted in CAR T-cell transduction, expansion, and elimination of systemic malignancy.ConclusionsThese findings demonstrate that UB-VV100 generates functional CAR T cells in vivo, which could expand patient access to CAR T technology in both hematological and solid tumors without the need for ex vivo cell manufacturing.

Native Americans are disproportionately affected by the criminal legal system, yet comparative analyses of criminal legal outcomes and experiences among racial and ethnic groups rarely center the experiences of Native Americans. This multimethod study examines how monetary sanctions are affecting Native American populations in Minnesota. Drawing on administrative criminal court data and qualitative fieldwork, we find that Native Americans are subject to among the largest overall legal financial obligations (LFOs) in criminal court and carry the largest average LFO debt loads relative to other racial and ethnic groups in Minnesota, particularly when proximal to tribal lands. Moreover, monetary sanctions exacerbate existing poverty and spatial isolation in rural areas, compounding and further entrenching historical, systemic disadvantages that Native communities already face. We contextualize these findings within the broader history of U. S. settler colonialism, resource extraction, and dispossession.

Psoriasis is an immune-mediated chronic inflammatory skin disease, characterized by epidermal hyperplasia and infiltration of leukocytes into the dermis and epidermis. IL-23 is expressed in psoriatic skin, and IL-23 injected into the skin of mice produces IL-22-dependent dermal inflammation and acanthosis. The chemokine receptor CCR2 has been implicated in the pathogenesis of several inflammatory diseases, including psoriasis. CCR2-positive cells and the CCR2 ligand, CCL2 are abundant in psoriatic lesions. To examine the requirement of CCR2 in the development of IL-23-induced cutaneous inflammation, we injected the ears of wild-type (WT) and CCR2-deficient (CCR2(-/-)) mice with IL-23. CCR2(-/-) mice had increased ear swelling and epidermal thickening, which was correlated with increased cutaneous IL-4 levels and increased numbers of eosinophils within the skin. In addition, TSLP, a cytokine known to promote and amplify T helper cell type 2 (Th2) immune responses, was also increased within the inflamed skin of CCR2(-/-) mice. Our data suggest that increased levels of TSLP in CCR2(-/-) mice may contribute to the propensity of these mice to develop increased Th2-type immune responses.

High levels of transcription in Saccharomyces cerevisiae are associated with increased genetic instability, which has been linked to DNA damage. Here, we describe a pGAL-CAN1 forward mutation assay for studying transcription-associated mutagenesis (TAM) in yeast. In a wild-type background with no alterations in DNA repair capacity, ≈50% of forward mutations that arise in the CAN1 gene under high-transcription conditions are deletions of 2–5 bp. Furthermore, the deletions characteristic of TAM localize to discrete hotspots that coincide with 2–4 copies of a tandem repeat. Although the signature deletions of TAM are not affected by the loss of error-free or error-prone lesion bypass pathways, they are completely eliminated by deletion of the TOP1 gene, which encodes the yeast type IB topoisomerase. Hotspots can be transposed into the context of a frameshift reversion assay, which is sensitive enough to detect Top1-dependent deletions even in the absence of high transcription. We suggest that the accumulation of Top1 cleavage complexes is related to the level of transcription and that their removal leads to the signature deletions. Given the high degree of conservation between DNA metabolic processes, the links established here among transcription, Top1, and mutagenesis are likely to extend beyond the yeast system.

The regulation of host–pathogen interactions during Mycobacterium tuberculosis (Mtb) infection remains unresolved. MicroRNAs (miRNAs) are important regulators of the immune system, and so we used a systems biology approach to construct an miRNA regulatory network activated in macrophages during Mtb infection. Our network comprises 77 putative miRNAs that are associated with temporal gene expression signatures in macrophages early after Mtb infection. In this study, we demonstrate a dual role for one of these regulators, miR-155. On the one hand, miR-155 maintains the survival of Mtb-infected macrophages, thereby providing a niche favoring bacterial replication; on the other hand, miR-155 promotes the survival and function of Mtb-specific T cells, enabling an effective adaptive immune response. MiR-155–induced cell survival is mediated through the SH2 domain-containing inositol 5-phosphatase 1 (SHIP1)/protein kinase B (Akt) pathway. Thus, dual regulation of the same cell survival pathway in innate and adaptive immune cells leads to vastly different outcomes with respect to bacterial containment.

In the 2015/2016 season, the close link between big budgets and soccer dominance broke down in the English Premier League. Here, a look at what motivated the surprise and why American-style sport socialism still isn’t likely to emerge in European leagues.

Dendritic cells (DCs) are critical in immune responses, linking innate and adaptive immunity. We found here that DC- specific deletion of the transcription factor STAT5 was not critical for development but was required for T helper type 2 ([T.sub.H.]2), but not TH1, allergic responses in both the skin and lungs. Loss of STAT5 in DCs led to the inability to respond to thymic stromal lymphopoietin (TSLP). STAT5 was required for TSLP-dependent DC activation, including upregulation of the expression of costimulatory molecules and chemokine production. Furthermore, [T.sub.H.]2 responses in mice with DC-specific loss of STAT5 resembled those seen in mice deficient in the receptor for TSLP. Our results show that the TSLP-STAT5 axis in DCs is a critical component for the promotion of type 2 immunity at barrier surfaces.

Nat. Immunol. 14, 364–371 (2013); published online 24 February 2013; corrected after print 23 September 2013 In the version of this article initially published, author Daniel H. Kaplan was not included. The correct list of authors and affiliations is as follows: Bryan D Bell1,2,7, Masayuki Kitajima1,2,7, Ryan P Larson1,2, Thomas A Stoklasek1,2, Kristen Dang1, Kazuhito Sakamoto3, Kay-Uwe Wagner3, Daniel H Kaplan4, Boris Reizis5, Lothar Hennighausen6 & Steven F Ziegler1,2