Journal: Science Immunology

Abbreviation

Sci Immunol

Publisher

AAAS

Journal Volumes

ISSN

2470-9468

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2017 - 201962020 - 202517
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Publications 1 - 10 of 23
  • Combined immunodeficiency with autoimmunity caused by a homozygous missense mutation in inhibitor of nuclear factor kappa B kinase alpha (IKK alpha)
    Item type: Journal Article
    Bainter, Wayne; Lougaris, Vassilios; Wallace, Jacqueline G.; et al. (2021)
    Science Immunology
    Inhibitor of nuclear factor kappa B kinase alpha (IKK alpha) is critical for p100/NF-kappa B2 phosphorylation and processing into p52 and activation of the noncanonical NF-kappa B pathway. A patient with recurrent infections, skeletal abnormalities, absent secondary lymphoid structures, reduced B cell numbers, hypogammaglobulinemia, and lymphocytic infiltration of intestine and liver was found to have a homozygous p.Y580C mutation in the helix-loop-helix domain of IKK alpha. The mutation preserves IKK alpha kinase activity but abolishes the interaction of IKK alpha with its activator NF-kappa B-inducing kinase and impairs lymphotoxin-beta-driven p100/NF-kappa B2 processing and VCAM1 expression. Homozygous IKK alpha(Y580C/Y580C) mutant mice phenocopy the patient findings; lack marginal zone B cells, germinal centers, and antigen-specific T cell response to cutaneous immunization; have impaired Il17a expression; and are susceptible to cutaneous Staphylococcus aureus infection. In addition, these mice demonstrate a severe reduction in medullary thymic epithelial cells, impaired thymocyte negative selection, a restricted TCRV beta repertoire, a selective expansion of potentially autoreactive T cell clones, a decreased frequency of regulatory T cells, and infiltration of liver, pancreas, and lung by activated T cells coinciding with organ damage. Hence, this study identifies IKK alpha deficiency as a previously undescribed cause of primary immunodeficiency with associated autoimmunity.
  • Modulation of asymmetric cell division as a mechanism to boost CD8+ T cell memory
    Item type: Journal Article
    Borsa, Mariana; Barnstorf, Isabel; Baumann, Nicolas S.; et al. (2019)
    Science Immunology
  • Sustained T follicular helper cell response is essential for control of chronic viral infection
    Item type: Journal Article
    Greczmiel, Ute; Kräutler, Nike Julia; Pedrioli, Alessandro; et al. (2017)
    Science Immunology
  • Protection against autoimmunity is driven by thymic epithelial cell–mediated regulation of Treg development
    Item type: Journal Article
    Haftmann, Claudia; Zwicky, Pascale; Ingelfinger, Florian; et al. (2021)
    Science Immunology
    Medullary thymic epithelial cells (mTECs) are key antigen-presenting cells mediating T cell tolerance to prevent harmful autoimmunity. mTECs both negatively select self-reactive T cells and promote the development of thymic regulatory T cells (tTregs) that mediate peripheral tolerance. The relative importance of these two mechanisms of thymic education to prevent autoimmunity is unclear. We generated a mouse model to specifically target the development and function of mTECs by conditional ablation of the NF-κB–inducing kinase (NIK) in the TEC compartment. In contrast to germline-deficient NIK-/- mice, Foxn1CreNIKfl/fl mice rapidly developed fatal T cell–dependent multiorgan autoimmunity shortly after birth. Thymic transplantation and adoptive transfer experiments demonstrated that autoimmunity arises specifically from the emergence of dysfunctional tTregs. Thus, Treg function, rather than negative selection, enforces the protection of peripheral tissues from autoimmune attack.
  • E-cadherin is regulated by GATA-2 and marks the early commitment of mouse hematopoietic progenitors to the basophil and mast cell fates
    Item type: Journal Article
    Wanet, Anaïs; Bassal, Mahmoud A.; Patel, Sweta B.; et al. (2021)
    Science Immunology
    E-cadherin is a calcium-dependent cell-cell adhesion molecule extensively studied for its involvement in tissue formation, epithelial cell behavior, and suppression of cancer. However, E-cadherin expression in the hematopoietic system has not been fully elucidated. Combining single-cell RNA-sequencing analyses and immunophenotyping, we revealed that progenitors expressing high levels of E-cadherin and contained within the granulocyte-monocyte progenitors (GMPs) fraction have an enriched capacity to differentiate into basophils and mast cells. We detected E-cadherin expression on committed progenitors before the expression of other reported markers of these lineages. We named such progenitors pro-BMPs (pro-basophil and mast cell progenitors). Using RNA sequencing, we observed transcriptional priming of pro-BMPs to the basophil and mast cell lineages. We also showed that GATA-2 directly regulates E-cadherin expression in the basophil and mast cell lineages, thus providing a mechanistic connection between the expression of this cell surface marker and the basophil and mast cell fate specification.
  • Response to Comment on "A subset of HLA-I peptides are not genomically templated: Evidence for cis- and trans-spliced peptide ligands"
    Item type: Journal Article
    Faridi, Pouya; Li, Chen; Ramarathinam, Sri H.; et al. (2019)
    Science Immunology
  • Human "TH9" cells are a subpopulation of PPAR-γ+ TH2 cells
    Item type: Journal Article
    Micossé, Claire; von Meyenn, Leonhard; Steck, Oliver; et al. (2019)
    Science Immunology
  • Exocrine gland–resident memory CD8⁺ T cells use mechanosensing for tissue surveillance
    Item type: Journal Article
    Ruef, Nora; Martínez Magdaleno, Jose; Ficht, Xenia Maria; et al. (2023)
    Science Immunology
    Tissue-resident CD8⁺ T cells (T_RM) continuously scan peptide-MHC (pMHC) complexes in their organ of residence to intercept microbial invaders. Recent data showed that T_RM lodged in exocrine glands scan tissue in the absence of any chemoattractant or adhesion receptor signaling, thus bypassing the requirement for canonical migration-promoting factors. The signals eliciting this noncanonical motility and its relevance for organ surveillance have remained unknown. Using mouse models of viral infections, we report that exocrine gland T_RM autonomously generated front-to-back F-actin flow for locomotion, accompanied by high cortical actomyosin contractility, and leading-edge bleb formation. The distinctive mode of exocrine gland T_RM locomotion was triggered by sensing physical confinement and was closely correlated with nuclear deformation, which acts as a mechanosensor via an arachidonic acid and Ca²⁺ signaling pathway. By contrast, naïve CD8⁺ T cells or T_RM surveilling microbe-exposed epithelial barriers did not show mechanosensing capacity. Inhibition of nuclear mechanosensing disrupted exocrine gland T_RM scanning and impaired their ability to intercept target cells. These findings indicate that confinement is sufficient to elicit autonomous T cell surveillance in glands with restricted chemokine expression and constitutes a scanning strategy that complements chemosensing-dependent migration.
  • Human LY9 governs CD4$^+$T cell IFN-γ immunity to Mycobacterium tuberculosis
    Item type: Journal Article
    Ogishi, Masato; Puchan, Julia; Yang, Rui; et al. (2025)
    Science Immunology
    CD4$^+$ T cells are indispensable for optimal immunity to Mycobacterium tuberculosis (M.tb), a pathogen that triggers tuberculosis (TB) in humans. M.tb-specific human CD4$^+$ T cells are known to polarize toward an interferon-γ (IFN-γ)-producing, CCR4$^-$CCR6$^+$CXCR3$^+$T-bet$^+$RORγT$^+$T helper 1* cell (T$_H$1*cell) memory phenotype. We report that autosomal recessive deficiency of the human lymphocytic surface receptor LY9 (SLAMF3 and CD229), which is found in less than 10$^{-5}$ individuals in the general population, underlies TB in three unrelated patients due to selective impairment in IFN-γ production by T$_H$1* cells. T$_H$1* cells express higher levels of LY9 than other CD4$^+$ T cells. Mechanistically, LY9 polarizes naïve CD4$^+$T cells toward memory T$_H$1* cells by inducing T-bet via signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) and RORγT (thymus-specific retinoid-related orphan receptor γ) without SAP. LY9 costimulation enhances TCR-driven IFN-γ production of memory T$_H$1*, but not T$_H$1, cells in a T cell-intrinsic manner via NFAT1 (nuclear factor of activated T cells 1) and RORγT. LY9 is likely to govern an optimal T$_H$1* cell- and IFN-γ-dependent protective immunity to M.tb in humans.
  • SARS-CoV-2 spike conformation determines plasma neutralizing activity elicited by a wide panel of human vaccines
    Item type: Journal Article
    Bowen, John E.; Park, Young-Jun; Stewart, Cameron; et al. (2022)
    Science Immunology
    Numerous safe and effective coronavirus disease 2019 vaccines have been developed worldwide that use various delivery technologies and engineering strategies. We show here that vaccines containing prefusion-stabilizing S mutations elicit antibody responses in humans with enhanced recognition of S and the S1 subunit relative to postfusion S as compared with vaccines lacking these mutations or natural infection. Prefusion S and S1 antibody binding titers positively and equivalently correlated with neutralizing activity, and depletion of S1-directed antibodies completely abrogated plasma neutralizing activity. We show that neutralizing activity is almost entirely directed to the S1 subunit and that variant cross-neutralization is mediated solely by receptor binding domain–specific antibodies. Our data provide a quantitative framework for guiding future S engineering efforts to develop vaccines with higher resilience to the emergence of variants than current technologies.
Publications 1 - 10 of 23