Journal: The Journal of Immunology

Abbreviation

J Immunol

Publisher

American Association of Immunologists

Journal Volumes

ISSN

0022-1767
1048-3233
1047-7381
1550-6606

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Publications 1 - 10 of 21
  • Diversity in Cortical Thymic Epithelial Cells Occurs through Loss of a Foxn1-Dependent Gene Signature Driven by Stage-Specific Thymocyte Cross-Talk
    Item type: Journal Article
    White, Andrea J.; Parnell, Sonia M.; Handel, Adam; et al. (2023)
    The Journal of Immunology
    In the thymus, cortical thymic epithelial cells (cTECs) and medullary thymic epithelial cells support αβT cell development from lymphoid progenitors. For cTECs, expression of a specialized gene signature that includes Cxcl12, Dll4, and Psmb11 enables the cortex to support T lineage commitment and the generation and selection of CD4⁺CD8⁺ thymocytes. Although the importance of cTECs in T cell development is well defined, mechanisms that shape the cTEC compartment and regulate its functional specialization are unclear. Using a Cxcl12ᴰˢᴿᵉᵈ reporter mouse model, we show that changes in Cxcl12 expression reveal a developmentally regulated program of cTEC heterogeneity. Although cTECs are uniformly Cxcl12ᴰˢᴿᵉᵈ⁺ during neonatal stages, progression through postnatal life triggers the appearance of Cxcl12ᴰˢᴿᵉᵈ⁻ cTECs that continue to reside in the cortex alongside their Cxcl12ᴰˢᴿᵉᵈ⁺ counterparts. This appearance of Cxcl12ᴰˢᴿᵉᵈ⁻ cTECs is controlled by maturation of CD4⁻CD8⁻, but not CD4⁺CD8⁺, thymocytes, demonstrating that stage-specific thymocyte cross-talk controls cTEC heterogeneity. Importantly, although fate-mapping experiments show both Cxcl12ᴰˢᴿᵉᵈ⁺ and Cxcl12ᴰˢᴿᵉᵈ⁻ cTECs share a common Foxn1⁺ cell origin, RNA sequencing analysis shows Cxcl12ᴰˢᴿᵉᵈ⁻ cTECs no longer express Foxn1, which results in loss of the FOXN1-dependent cTEC gene signature and may explain the reduced capacity of Cxcl12ᴰˢᴿᵉᵈ⁻ cTECs for thymocyte interactions. In summary, our study shows that shaping of the cTEC compartment during the life course occurs via stage-specific thymocyte cross-talk, which drives loss of Foxn1 expression and its key target genes, which may then determine the functional competence of the thymic cortex.
  • TLR ligands act directly upon T cells to restore proliferation in the absence of protein kinase C-theta signaling and promote autoimmune myocarditis
    Item type: Journal Article
    Marsland, Benjamin J.; Nembrini, Chiara; Grün, Katja; et al. (2007)
    The Journal of Immunology
  • Activin A Promotes the TGF-β-Induced Conversion of CD4+CD25– T Cells into Foxp3+ Induced Regulatory T Cells
    Item type: Journal Article
    Huber, Samuel; Stahl, Felix R.; Schrader, Jörg; et al. (2009)
    The Journal of Immunology
    TGF-β induces the conversion of CD4+CD25− T cells into CD4+CD25+Foxp3+ regulatory T cells (Treg). Activin A is a pleiotropic TGF-β family member and is expressed in response to inflammatory signals. In this study, we report on the effects of activin A on the conversion of CD4+CD25− T cells into Foxp3-expressing induced Treg (iTreg). Activin A was able to promote the conversion of CD4+CD25− T cells into iTreg in a dose-dependent manner in vitro. Activin A together with TGF-β1 had synergistic effects on the rate of iTreg conversion in vitro. Intact TGF-β1 signaling seemed to be essential for the effects of activin A on iTreg generation because cells overexpressing a dominant negative TGF-β type II receptor could not be converted by activin A in vitro. In vivo, the frequency of peripheral, but not central, Treg was increased in transgenic mice with elevated activin A serum levels and the in vivo conversion rate of CD4+CD25− T cells into Foxp3-expressing iTreg was increased as compared with wild type mice. These data suggest a role for activin A as a promoter of the TGF-β dependent conversion of CD4+CD25− T cells into iTreg in vitro and in vivo. Therefore, besides promoting inflammation, activin A may contribute to the regulation of inflammation via the expansion of peripheral Treg.
  • A novel role for neutrophils as critical activators of NK Cells
    Item type: Journal Article
    Spörri, Roman; Joller, Nicole; Hilbi, Hubert; et al. (2008)
    The Journal of Immunology
  • A Rapid Translational Immune Response Program in CD8 Memory T Lymphocytes
    Item type: Journal Article
    Salloum, Darin; Singh, Kamini; Davidson, Natalie R.; et al. (2022)
    The Journal of Immunology
    The activation of memory T cells is a very rapid and concerted cellular response that requires coordination between cellular processes in different compartments and on different time scales. In this study, we use ribosome profiling and deep RNA sequencing to define the acute mRNA translation changes in CD8 memory T cells following initial activation events. We find that initial translation enables subsequent events of human and mouse T cell activation and expansion. Briefly, early events in the activation of Ag-experienced CD8 T cells are insensitive to transcriptional blockade with actinomycin D, and instead depend on the translation of pre-existing mRNAs and are blocked by cycloheximide. Ribosome profiling identifies ∼92 mRNAs that are recruited into ribosomes following CD8 T cell stimulation. These mRNAs typically have structured GC and pyrimidine-rich 5' untranslated regions and they encode key regulators of T cell activation and proliferation such as Notch1, Ifngr1, Il2rb, and serine metabolism enzymes Psat1 and Shmt2 (serine hydroxymethyltransferase 2), as well as translation factors eEF1a1 (eukaryotic elongation factor α1) and eEF2 (eukaryotic elongation factor 2). The increased production of receptors of IL-2 and IFN-γ precedes the activation of gene expression and augments cellular signals and T cell activation. Taken together, we identify an early RNA translation program that acts in a feed-forward manner to enable the rapid and dramatic process of CD8 memory T cell expansion and activation.
  • Advancing Antibody Engineering through Synthetic Evolution and Machine Learning
    Item type: Journal Article
    Irvine, Edward B.; Reddy, Sai T. (2024)
    The Journal of Immunology
    Abs are versatile molecules with the potential to achieve exceptional binding to target Ags, while also possessing biophysical properties suitable for therapeutic drug development. Protein display and directed evolution systems have transformed synthetic Ab discovery, engineering, and optimization, vastly expanding the number of Ab clones able to be experimentally screened for binding. Moreover, the burgeoning integration of high-throughput screening, deep sequencing, and machine learning has further augmented in vitro Ab optimization, promising to accelerate the design process and massively expand the Ab sequence space interrogated. In this Brief Review, we discuss the experimental and computational tools employed in synthetic Ab engineering and optimization. We also explore the therapeutic challenges posed by developing Abs for infectious diseases, and the prospects for leveraging machine learning-guided protein engineering to prospectively design Abs resistant to viral escape.
  • An Antigen Capture Assay for the Detection of Mycolactone, the Polyketide Toxin of Mycobacterium ulcerans
    Item type: Journal Article
    Warryn, Louisa; Dangy, Jean-Pierre; Gersbach, Philipp; et al. (2021)
    The Journal of Immunology
    Mycolactone is a cytotoxin responsible for most of the chronic necrotizing pathology of Mycobacterium ulcerans disease (Buruli ulcer). The polyketide toxin consists of a 12-membered lactone ring with a lower O-linked polyunsaturated acyl side chain and an upper C-linked side chain. Mycolactone is unique to M. ulcerans and an immunological Ag capture assay would represent an important tool for the study of Buruli ulcer pathogenesis and for laboratory diagnosis. When testing sets of mycolactone-specific mouse mAbs, we found that Abs against the hydrophobic lower side chain only bind mycolactone immobilized on a solid support but not when present in solution. This observation supports previous findings that mycolactone forms micellar structures in aqueous solution with the hydrophobic region sequestered into the inner core of the aggregates. Although an Ag capture assay typically requires two Abs that recognize nonoverlapping epitopes, our search for matching pairs of mAbs showed that the same mAb could be used both as capture and as detecting reagent for the detection of the mycolactone aggregates. However, the combination of a core-specific and a core/upper side chain_specific mAb constituted the most sensitive ELISA with a sensitivity in the low nanogram range. The results of a pilot experiment showed that the sensitivity of the assay is sufficient to detect mycolactone in swab samples from Buruli ulcer lesions. Although the described capture ELISA can serve as a tool for research on the biology of mycolactone, the assay system will have to be adapted for use as a diagnostic tool.
  • Cutting Edge: IL-17-Secreting Innate Lymphoid Cells Are Essential for Host Defense against Fungal Infection
    Item type: Journal Article
    Gladiator, A.; Wangler, N.; Trautwein-Weidner, K.; et al. (2013)
    The Journal of Immunology
  • CD4(+) and CD8(+) T Cells Exhibit Differential Requirements for CCR7-Mediated Antigen Transport during Influenza Infection
    Item type: Journal Article
    Heer, Alex K.; Harris, Nicola L.; Kopf, Manfred; et al. (2008)
    The Journal of Immunology
  • An Innate Checkpoint Determines Immune Dysregulation and Immunopathology during Pulmonary Murine Coronavirus Infection
    Item type: Journal Article
    Grabherr, Sarah; Waltenspühl, Alexandra; Büchler, Lorina; et al. (2023)
    The Journal of Immunology
    Hallmarks of life-threatening, coronavirus-induced disease include dysregulated antiviral immunity and immunopathological tissue injury. Nevertheless, the sampling of symptomatic patients overlooks the initial inflammatory sequela culminating in severe coronavirus-induced disease, leaving a fundamental gap in our understanding of the early mechanisms regulating anticoronavirus immunity and preservation of tissue integrity. In this study, we delineate the innate regulators controlling pulmonary infection using a natural mouse coronavirus. Within hours of infection, the cellular landscape of the lung was transcriptionally remodeled altering host metabolism, protein synthesis, and macrophage maturation. Genetic perturbation revealed that these transcriptional programs were type I IFN dependent and critically controlled both host cell survival and viral spread. Unrestricted viral replication overshooting protective IFN responses culminated in increased IL-1β and alarmin production and triggered compensatory neutrophilia, interstitial inflammation, and vascular injury. Thus, type I IFNs critically regulate early viral burden, which serves as an innate checkpoint determining the trajectory of coronavirus dissemination and immunopathology.
Publications 1 - 10 of 21