Immune deficiencies, infection, and systemic immune disorders
Impaired T-cell receptor activation in IL-1 receptor–associated kinase-4–deficient patients

https://doi.org/10.1016/j.jaci.2010.05.013Get rights and content

Background

IL-1 receptor–associated kinase 4 (IRAK-4) is an effector of the Toll-like receptor and IL-1 receptor pathways that plays a critical role in innate immune responses. The role of IRAK-4 in adaptive immune functions in human subjects is incompletely understood.

Objective

We sought to evaluate T-cell function in IRAK-4 deficient patients.

Methods

We compared upregulation of CD25 and CD69 on T cells and production of IL-2, IL-6, and IFN-γ after stimulation of PBMCs from 4 IRAK-4–deficient patients and healthy control subjects with anti-CD3 and anti-CD28.

Results

Upregulation of CD25 and CD69 on T cells and production of IL-6 and IFN-γ, but not IL-2, was significantly reduced in IRAK-4–deficient patients.

Conclusions

IRAK-4–deficient patients have defects in T-cell activation.

Section snippets

Subjects

Four unrelated patients with IRAK-4 deficiency with distinct molecular defects were studied.6, 11, 12 All had clinical features of IRAK-4 deficiency, and the diagnosis was confirmed by means of molecular analysis. Parents of all subjects enrolled in these studies signed informed consent forms that were approved by the University of Iowa Children's Hospital Institutional Review Board and Children's Hospital, Boston, and in accordance with the Declaration of Helsinki. Case reports are included in

Impaired TLR and IL-1 receptor signaling in a compound heterozygous IRAK-4–deficient patient

The clinical history of the index patient is detailed in this article's Online Repository. Severe and recurrent pyogenic infections and a diminished febrile response to invasive bacterial infections suggested a defect in innate immunity. Stimulation of the patient's blood cells with TLR ligands failed to elicit production of TNF-α (Fig 1, A). TLRs and IL-1 receptor use the adaptor MyD88 and IRAK-4 to activate IKK, which phosphorylates the NF-κBα inhibitor IκBα. Stimulation of the patient's

Discussion

The results of this study support a role for IRAK-4 in T-cell activation. Stimulation of T cells through the TCR leads to upregulation of CD69 and CD25, which are early markers of T-cell activation.15, 16 Upregulation of the activation markers CD25 and CD69 after TCR ligation and ligation of both the TCR and CD28 was impaired in all 4 IRAK-4–deficient patients analyzed. CD69 is the earliest marker of lymphocyte activation and might be involved in lymphocyte proliferation. CD25 is a component of

References (27)

  • N. Suzuki et al.

    A critical role for the innate immune signaling molecule IRAK-4 in T cell activation

    Science

    (2006)
  • T. Kawagoe et al.

    Essential role of IRAK-4 protein and its kinase activity in Toll-like receptor-mediated immune responses but not in TCR signaling

    J Exp Med

    (2007)
  • E. Lye et al.

    IRAK-4 kinase activity is required for IRAK-4-dependent innate and adaptive immune responses

    Eur J Immunol

    (2008)
  • Cited by (12)

    • Inhibition of IL-1 Receptor-Associated Kinase 1 Decreases Murine Acute Graft-versus-Host Disease While Preserving the Graft-versus-Lymphoma Effect

      2022, Transplantation and Cellular Therapy
      Citation Excerpt :

      Moreover, T-cell's-derived IRAK is important for its activation induced by the IL-1 cytokine family [12]. IRAK-deficient humans have defects in T cell activation, as indicated by decreased expression of CD69 and IFNγ [13]. IRAK regulates GM-CSF production in T cells and has an impact on the differentiation of effector T cells [14].

    • IRAK family in inflammatory autoimmune diseases

      2020, Autoimmunity Reviews
      Citation Excerpt :

      Secretion of IL-17, IFN-γ, frequency of CD4+IFN-γ+, CD4+IL-17+ T cells, phosphorylation of NF-κB, STAT1, STAT3 were elevated in CD4+ T cells from normal people in the presence of IL-18, IL-1β, whereas the responses were abolished upon administration of IRAK4 inhibitor [71]. CD4+, CD8+ T cells from normal people treated with CD3, CD28 up-regulated expression of CD25, CD69, but was impaired in the patient with IRAK4 deficiency, and the percentage of CD4+CD25+, CD8+CD25+, CD4+CD69+, CD8+CD69+ T cells was reduced in IRAK4−/− people [72]. With respect to role of IRAK4 in mice, CD8+ T cells from IRAK4−/−, IRAK4 KI mice infected with lymphocytic choriomeningitis virus (LCMV) impaired the ability to expansion, down-regulated NF-κB activation, PKC phosphorylation, NF-κBp65 nuclear translocation, IκBα induction [36,73].

    • Other TLR Pathway Defects

      2014, Stiehm's Immune Deficiencies
    • Advances in basic and clinical immunology in 2010

      2011, Journal of Allergy and Clinical Immunology
      Citation Excerpt :

      This report reminds us that gene defects can occur in regulatory regions that are not commonly examined and that the clinical diagnosis might not be ruled out by initial genetic testing. McDonald et al29 studied a patient with IL-1 receptor–associated kinase 4 deficiency to illustrate the importance of TLR stimulation in T-cell activation. Compared with cells from a healthy donor, the expression of the activation markers CD25 and CD69 by this patient’s T cells were both decreased by half when activating with anti-CD3 and anti-CD28 antibodies, which target the TCR, but were normal when stimulation with phorbol 12-myristate 13-acetate and ionomycin was used.

    View all citing articles on Scopus

    Supported by National Institutes of Health grant 5KO8AI76625 (D. R. M.) and National Institutes of Health grant PO1AI035714 (R. S. G.).

    Disclosure of potential conflict of interest: R. S. Geha has received research support from the National Institutes of Health. The rest of the authors have declared that they have no conflict of interest.

    These authors contributed equally to this work.

    View full text