Abnormal regulation of interferon-γ, interleukin-12, and tumor necrosis factor-α in human interferon-γ receptor 1 deficiency

Mycobacterial infections are critically controlled by interferon-γ (IFN-γ) and the cellular responses it elaborates, as shown by patients with mutations in the IFN-γ receptor ligand-binding chain (IFN-γR1) who have disseminated nontuberculous mycobacterial infections. The immunologic sequelae of IFN-γR1 deficiency were characterized in 2 unrelated patients from the Indian subcontinent with novel homozygous recessive IFN-γR1 mutations. In vitro, these patients' peripheral blood mononuclear cells produced 10% of normal IFN-γ and interleukin-12 (IL-12) in response to phytohemagglutinin (PHA) but normal amounts of IFN-γ in response to PHA plus IL-12. Tumor necrosis factor-α (TNF-α) production was normal in response to endotoxin and to PHA but was not augmented by the addition of IFN-γ. An abnormal phenotype was not found in heterozygous patient relatives. These patients demonstrate the critical role that the IFN-γ receptor plays in the regulation of IFN-γ, IL-12, and TNF-α.