Tolerogenic function of Blimp-1 in dendritic cellsKim, Sun Jung; Zou, Yong Rui; Goldstein, Jordan; Reizis, Boris; Diamond, Betty
doi: 10.1084/jem.20110658pmid: 21948081
Blimp-1 has been identified as a key regulator of plasma cell differentiation in B cells and effector/memory function in T cells. We demonstrate that Blimp-1 in dendritic cells (DCs) is required to maintain immune tolerance in female but not male mice. Female mice lacking Blimp-1 expression in DCs (DCBlimp-1 ko ) or haploid for Blimp-1 expression exhibit normal DC development but an altered DC function and develop lupus-like autoantibodies. Although DCs have been implicated in the pathogenesis of lupus, a defect in DC function has not previously been shown to initiate the disease process. Blimp-1 ko DCs display increased production of IL-6 and preferentially induce differentiation of follicular T helper cells (T FH cells) in vitro. In vivo, the expansion of T FH cells is associated with an enhanced germinal center (GC) response and the development of autoreactivity. These studies demonstrate a critical role for Blimp-1 in the tolerogenic function of DCs and show that a diminished expression of Blimp-1 in DCs can result in aberrant activation of the adaptive immune system with the development of a lupus-like serology in a gender-specific manner. This study is of particular interest because a polymorphism of Blimp-1 associates with SLE. Submitted: 1 April 2011 Accepted: 24 August 2011 This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms ). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ ).
Regulation of neutrophils by interferon-γ limits lung inflammation during tuberculosis infectionNandi, Bisweswar; Behar, Samuel M.
doi: 10.1084/jem.20110919pmid: 21967766
Resistance to Mycobacterium tuberculosis requires the host to restrict bacterial replication while preventing an over-exuberant inflammatory response. Interferon (IFN) γ is crucial for activating macrophages and also regulates tissue inflammation. We dissociate these two functions and show that IFN-γ −/− memory CD4 + T cells retain their antimicrobial activity but are unable to suppress inflammation. IFN-γ inhibits CD4 + T cell production of IL-17, which regulates neutrophil recruitment. In addition, IFN-γ directly inhibits pathogenic neutrophil accumulation in the infected lung and impairs neutrophil survival. Regulation of neutrophils is important because their accumulation is detrimental to the host. We suggest that neutrophilia during tuberculosis indicates failed Th1 immunity or loss of IFN-γ responsiveness. These results establish an important antiinflammatory role for IFN-γ in host protection against tuberculosis. Submitted: 6 May 2011 Accepted: 31 August 2011 This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms ). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ ).
Transcytosis of Listeria monocytogenes across the intestinal barrier upon specific targeting of goblet cell accessible E-cadherinNikitas, Georgios; Deschamps, Chantal; Disson, Olivier; Niault, Théodora; Cossart, Pascale; Lecuit, Marc
doi: 10.1084/jem.20110560pmid: 21967767
Listeria monocytogenes ( Lm ) is a foodborne pathogen that crosses the intestinal barrier upon interaction between its surface protein InlA and its species-specific host receptor E-cadherin (Ecad). Ecad, the key constituent of adherens junctions, is typically situated below tight junctions and therefore considered inaccessible from the intestinal lumen. In this study, we investigated how Lm specifically targets its receptor on intestinal villi and crosses the intestinal epithelium to disseminate systemically. We demonstrate that Ecad is luminally accessible around mucus-expelling goblet cells (GCs), around extruding enterocytes at the tip and lateral sides of villi, and in villus epithelial folds. We show that upon preferential adherence to accessible Ecad on GCs, Lm is internalized, rapidly transcytosed across the intestinal epithelium, and released in the lamina propria by exocytosis from where it disseminates systemically. Together, these results show that Lm exploits intrinsic tissue heterogeneity to access its receptor and reveal transcytosis as a novel and unanticipated pathway that is hijacked by Lm to breach the intestinal epithelium and cause systemic infection. Submitted: 21 March 2011 Accepted: 1 September 2011 This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms ). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ ).
A live-attenuated chlamydial vaccine protects against trachoma in nonhuman primatesKari, Laszlo; Whitmire, William M.; Olivares-Zavaleta, Norma; Goheen, Morgan M.; Taylor, Lacey D.; Carlson, John H.; Sturdevant, Gail L.; Lu, Chunxue; Bakios, Lauren E.; Randall, Linnell B.; Parnell, Michael J.; Zhong, Guangming; Caldwell, Harlan D.
doi: 10.1084/jem.20111266pmid: 21987657
Blinding trachoma is an ancient neglected tropical disease caused by Chlamydia trachomatis for which a vaccine is needed. We describe a live-attenuated vaccine that is safe and efficacious in preventing trachoma in nonhuman primates, a model with excellent predictive value for humans. Cynomolgus macaques infected ocularly with a trachoma strain deficient for the 7.5-kb conserved plasmid presented with short-lived infections that resolved spontaneously without ocular pathology. Multiple infections with the attenuated plasmid-deficient strain produced no inflammatory ocular pathology but induced an anti-chlamydial immune response. Macaques vaccinated with the attenuated strain were either solidly or partially protected after challenge with virulent plasmid-bearing organisms. Partially protected macaques shed markedly less infectious organisms than controls. Immune correlates of protective immunity were not identified, but we did detect a correlation between MHC class II alleles and solid versus partial protection. Epidemiological models of trachoma control indicate that a vaccine with this degree of efficacy would significantly reduce the prevalence of infection and rates of reinfection, known risk factors which drive blinding disease. Submitted: 20 June 2011 Accepted: 8 September 2011 This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms ). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ ).
Assembling defenses against therapy-resistant leukemic stem cells: Bcl6 joins the ranksPellicano, Francesca; Holyoake, Tessa L.
doi: 10.1084/jem.20112087pmid: 22025499
The resistance of leukemic stem cells in response to targeted therapies such as tyrosine kinase inhibitors (TKIs) relies on the cooperative activity of multiple signaling pathways and molecules, including TGFβ, AKT, and FOXO transcription factors (TFs). B cell lymphoma 6 (BCL6) is a transcriptional repressor whose translocation or mutation is associated with diffuse large BCL. New data now show that BCL6 is critical for the maintenance of leukemias driven by the BCR-ABL translocation (Philadelphia chromosome), suggesting that BCL6 is a novel, targetable member of the complex signaling pathways critical for leukemic stem cell survival. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms ). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ ).
Unraveling the basic biology and clinical significance of the chlamydial plasmidRockey, Daniel D.
doi: 10.1084/jem.20112088pmid: 22025500
Chlamydial plasmids are small, highly conserved, nonconjugative, and nonintegrative DNA molecules that are nearly ubiquitous in many chlamydial species, including Chlamydia trachomatis . There has been significant recent progress in understanding chlamydial plasmid participation in host–microbe interactions, disease, and immune responses. Work in mouse model systems and, very recently, in nonhuman primates demonstrates that plasmid-deficient chlamydial strains function as live attenuated vaccines against genital and ocular infections. Collectively, these studies open new avenues of research into developing vaccines against trachoma and sexually transmitted chlamydial infections. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms ). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ ).