bims-actimu Biomed News
on Actinopathies in inborn errors of immunity
Issue of 2024–08–11
two papers selected by
Elodie Busch, University of Strasbourg
  1. DIAPH1-Deficiency is Associated with Major T, NK and ILC Defects in Humans.
  2. B cells require DOCK8 to elicit and integrate T cell help when antigen is limiting.
  1. J Clin Immunol. 2024 Aug 09. 44(8): 175
    DIAPH1-Deficiency is Associated with Major T, NK and ILC Defects in Humans.
    Zehra Busra Azizoglu, Royala Babayeva, Zehra Sule Haskologlu, Mustafa Burak Acar, Serife Ayaz-Guner, Fatma Zehra Okus, Mohammad Bilal Alsavaf, Salim Can, Kemal Erdem Basaran, Mehmed Fatih Canatan, Alper Ozcan, Hasret Erkmen, Can Berk Leblebici, Ebru Yilmaz, Musa Karakukcu, Mehmet Kose, Ozlem Canoz, Ahmet Özen, Elif Karakoc-Aydiner, Serdar Ceylaner, Gülsüm Gümüş, Huseyin Per, Hakan Gumus, Halit Canatan, Servet Ozcan, Figen Dogu, Aydan Ikinciogullari, Ekrem Unal, Safa Baris, Ahmet Eken.
      Loss of function mutations in Diaphanous related formin 1 (DIAPH1) are associated with seizures, cortical blindness, and microcephaly syndrome (SCBMS) and are recently linked to combined immunodeficiency. However, the extent of defects in T and innate lymphoid cells (ILCs) remain unexplored. Herein, we characterized the primary T, natural killer (NK) and helper ILCs of six patients carrying two novel loss of function mutation in DIAPH1 and Jurkat cells after DIAPH1 knockdown. Mutations were identified by whole exome sequencing. T-cell immunophenotyping, proliferation, migration, cytokine signaling, survival, and NK cell cytotoxicity were studied via flow cytometry-based assays, confocal microscopy, and real-time qPCR. CD4+ T cell proteome was analyzed by mass spectrometry. p.R351* and p.R322*variants led to a significant reduction in the DIAPH1 mRNA and protein levels. DIAPH1-deficient T cells showed proliferation, activation, as well as TCR-mediated signaling defects. DIAPH1-deficient PBMCs also displayed impaired transwell migration, defective STAT5 phosphorylation in response to IL-2, IL-7 and IL-15. In vitro generation/expansion of Treg cells from naïve T cells was significantly reduced. shRNA-mediated silencing of DIAPH1 in Jurkat cells reduced DIAPH1 protein level and inhibited T cell proliferation and IL-2/STAT5 axis. Additionally, NK cells from patients had diminished cytotoxic activity, function and IL-2/STAT5 axis. Lastly, DIAPH1-deficient patients' peripheral blood contained dramatically reduced numbers of all helper ILC subsets. DIAPH1 deficiency results in major functional defects in T, NK cells and helper ILCs underlining the critical role of formin DIAPH1 in the biology of those cell subsets.
    Keywords:  Cytoskeletal defects; DIAPH1; Immunodeficiency; Macrothrombocytopenia
    DOI:  https://doi.org/10.1007/s10875-024-01777-8
  2. Sci Immunol. 2024 Aug 09. 9(98): eadd4874
    B cells require DOCK8 to elicit and integrate T cell help when antigen is limiting.
    Mukta Deobagkar-Lele, Greg Crawford, Tanya L Crockford, Jennifer Back, Rose Hodgson, Aneesha Bhandari, Katherine R Bull, Richard J Cornall.
      Dedicator of cytokinesis 8 (DOCK8) immunodeficiency syndrome is characterized by a failure of the germinal center response, a process involving the proliferation and positive selection of antigen-specific B cells. Here, we describe how DOCK8-deficient B cells are blocked at a light-zone checkpoint in the germinal centers of immunized mice, where they are unable to respond to T cell-dependent survival and selection signals and consequently differentiate into plasma cells or memory B cells. Although DOCK8-deficient B cells can acquire and present antigen to initiate activation of cognate T cells, integrin up-regulation, B cell-T cell conjugate formation, and costimulation are insufficient for sustained B cell and T cell activation when antigen availability is limited. Our findings provide an explanation for the failure of the humoral response in DOCK8 immunodeficiency syndrome and insight into how the level of available antigen modulates B cell-T cell cross-talk to fine-tune humoral immune responses and immunological memory.
    DOI:  https://doi.org/10.1126/sciimmunol.add4874
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