CD48 is expressed on nearly all cells of haematopoietic origin. CD48 interacts with the 2B4 receptor on NK cells, γδ T lymphocytes and activated cytotoxic T lymphocytes. In humans, 2B4 acts as an activating receptor. Phenotypes of an inherited defect in CD48 have never been described in humans. In a patient suffering from recurrent episodes of fever, rash, bi-cytopenia, hyperferritinaemia and IL-6 hypercytokinaemia, we found a heterozygous mutation in CD48. We sought to assess the consequences of the mutation on CD48 expression, cytotoxic effectiveness and systemic inflammation.
We performed whole exome sequencing on DNA samples of the patient, his brother and parents. RNA and protein expression were measured; flow cytometry and NK-cell killing assays of patient’s cells and killing assays of a transfected cell line were conducted. Signs for systemic inflammation were assessed in lymphocytic choriomeningitis virus (LCMV)-infected CD48-mutant mice.
The patient’s heterozygous mutation led to reduced cell surface expression of CD48, thereby reducing susceptibility to NK-cell mediated killing. A murine model was used to assess the effect of germline CD48 mutation in immune regulation. Viral infection induced hyperferritinaemia and IL-6 hypercytokinaemia in CD48-deficient mice, similar to the pattern observed in the patient during flares.
Our results show that reduced CD48-expression may lead to immune dysregulation. One possible explanation for this immune dysregulation is that the decreased CD48 expression on target cells enables their escape from killing, thereby interfering with the immune-regulatory function of cytotoxic lymphocytes.