Severe Mycobacterial and <i>Salmonella</i> Infections in Interleukin-12 Receptor-Deficient Patients

TLDR

Interleukin‑12 drives cell‑mediated immunity to intracellular pathogens by inducing TH1 responses and IFN‑γ production through binding to β1/β2 heterodimeric receptors on T and NK cells. Three unrelated patients with severe mycobacterial and Salmonella infections lacked IL‑12Rβ1 expression due to premature stop‑codon mutations, leading to defective IL‑12 signaling, impaired IFN‑γ production, and confirming IL‑12’s essential role in resistance to intracellular bacterial infections.

Abstract

Interleukin-12 (IL-12) is a cytokine that promotes cell-mediated immunity to intracellular pathogens by inducing type 1 helper T cell (T H 1) responses and interferon-γ (IFN-γ) production. IL-12 binds to high-affinity β1/β2 heterodimeric IL-12 receptor (IL-12R) complexes on T cell and natural killer cells. Three unrelated individuals with severe, idiopathic mycobacterial and S almonella infections were found to lack IL-12Rβ1 chain expression. Their cells were deficient in IL-12R signaling and IFN-γ production, and their remaining T cell responses were independent of endogenous IL-12. IL-12Rβ1 sequence analysis revealed genetic mutations that resulted in premature stop codons in the extracellular domain. The lack of IL-12Rβ1 expression results in a human immunodeficiency and shows the essential role of IL-12 in resistance to infections due to intracellular bacteria.