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Cited by 55T-cell and B-cell ImmunologyImmunodeficiency and Autoimmune DisordersProtein Kinase Regulation and GTPase Signaling

A point mutation in the murine Hem1 gene reveals an essential role for Hematopoietic Protein 1 in lymphopoiesis and innate immunity

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Park, Heon, Staehling-Hampton, Karen, Appleby, Mark W., Brunkow, Mary E., Habib, Tania, Zhang, Yi, Ramsdell, Fred, Liggitt, H. Denny +6 more·2008·The Journal of Experimental Medicine
DOI 10.1084/jem.20080340PMC PMC2585840
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Abstract

Hem1 (Hematopoietic protein 1) is a hematopoietic cell-specific member of the Hem family of cytoplasmic adaptor proteins. Orthologues of Hem1 in Dictyostelium discoideum, Drosophila melanogaster, and Caenorhabditis elegans are essential for cytoskeletal reorganization, embryonic cell migration, and morphogenesis. However, the in vivo functions of mammalian Hem1 are not known. Using a chemical mutagenesis strategy in mice to identify novel genes involved in immune cell functions, we positionally cloned a nonsense mutation in the Hem1 gene. Hem1 deficiency results in defective F-actin polymerization and actin capping in lymphocytes and neutrophils caused by loss of the Rac-controlled actin-regulatory WAVE protein complex. T cell development is disrupted in Hem1-deficient mice at the CD4−CD8− (double negative) to CD4+CD8+ (double positive) cell stages, whereas T cell activation and adhesion are impaired. Hem1-deficient neutrophils fail to migrate in response to chemotactic agents and are deficient in their ability to phagocytose bacteria. Remarkably, some Rac-dependent functions, such as Th1 differentiation and nuclear factor κB (NF-κB)–dependent transcription of proinflammatory cytokines proceed normally in Hem1-deficient mice, whereas the production of Th17 cells are enhanced. These results demonstrate that Hem1 is essential for hematopoietic cell development, function, and homeostasis by controlling a distinct pathway leading to cytoskeletal reorganization, whereas NF-κB–dependent transcription proceeds independently of Hem1 and F-actin polymerization.

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  • Two unrelated HEM1-deficient patients displayed persistently elevated proportions of αβ double-negative T cells.

    “Two unrelated patients displayed persistently elevated proportions of αβ double-negative T (DNT) cells, an interesting comparison to the hallmark expansion of DNTs in autoimmune lymphoproliferative syndrome [8, 31, 32].”

    From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [32]

    The Results section on bone-marrow chimeras reports that most thymic cells derived from Hem1-deficient mouse donors remained at the double-negative stage. The paper does not report two unrelated human patients, persistently elevated proportions of αβ double-negative T cells, or the claimed patient-level finding. (LLM, conf=0.82)

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  • Defects in neutrophil, dendritic cell, and macrophage migration and phagocytosis impair innate immune defenses, predisposing HEM1-deficient patients to bacterial infections.

    “Like mouse models of HEM1 deficiency, defects in neutrophil, dendritic cell, and macrophage migration and phagocytosis impair innate immune defenses, predisposing patients to bacterial infections [32–35].”

    From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [32]

    The Results section ('Hem1 is required for migration, phagocytosis, and F-actin polymerization in neutrophils'; page unavailable) reports impaired migration and phagocytosis in Hem1-deficient mouse neutrophils and impaired bacterial phagocytosis in mouse macrophages. The Discussion links these defects to impaired innate immune function. This paper does not establish dendritic-cell defects or show that these defects predispose human patients to bacterial infections. (LLM, conf=0.88)

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Authors
Park, H., Staehling-Hampton, K., Appleby, M. W., Brunkow, M. E., Habib, T., Zhang, Y., Ramsdell, F., Liggitt, H. D., Freie, B., Tsang, M., Carlson, G., Friend, S., Frevert, C., & Iritani, B. M.
Affiliations
  • University of Washington (US)
  • 2Celltech R & D, Inc., Bothell, WA 98021
  • Fred Hutch Cancer Center (US)
  • McLaughlin Research Institute (US)
  • 5Amnis, Inc., Seattle, WA 98121
ORCID
Venue
The Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
2008-11-17
Volume
205
Issue
12
Pages
2899-2913
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
DOI
10.1084/jem.20080340
PMC
PMC2585840
OpenAlex
W2140722334
Cited by
55
References
1
Citations by year
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FWCI
0.79
Type
journal article
Language
en
Open access
Locations
  • The Journal of Experimental Medicine (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Funders
  • University of Washington
  • National Institutes of Health (8k26od011060-05)
  • National Institute of Allergy and Infectious Diseases (R01AI0535468)
  • National Center for Research Resources (K26RR024462)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
lymphocyte development, T cell development, F-actin polymerization, actin filament capping, WAVE complex, Rac, neutrophil chemotaxis, phagocytosis, Th17 cells, NF-κB transcription, innate immunity, cytoskeletal remodeling, nonsense mutation
MeSH terms
Actins, Anemia, Animals, B-Lymphocytes, Cell Movement, DNA Mutational Analysis, Hematopoietic Stem Cells, Hematopoietic System, Immunity, Innate, Interferon-gamma, Interleukin-2, Lymphocyte Activation, Lymphopenia, Male, Membrane Proteins, Mice, Inbred C57BL, Neutrophils, Phagocytosis, T-Lymphocytes, Point Mutation, Transplantation Chimera, Mice, Knockout, Interleukin-17, Lymphopoiesis, Adaptor Proteins, Signal Transducing, Mice

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