IL-12-Independent Costimulation Pathways for Interferon-γ Production in Familial DisseminatedMycobacterium aviumComplex Infection

We have described previously a family with an apparent genetic susceptibility to disseminatedMycobacterium aviumcomplex infection and an underlying defect in IL-12 regulation leading to abnormally low interferon-γ production. Their T cells appear to act normally when in the presence of normal accessory cells. Cell-to-cell contact was necessary for normal monocytes to complement the familial patient monocyte defect, suggesting the familial defect in interferon-γ costimulation involves pathways requiring cell surface molecule interactions. In an effort to better characterize the abnormality in these patients, we examined the role of known costimulatory molecules in residual costimulation by patient PBMC compared to normals. Whereas normals utilized CD40/CD40L interactions and IL-12 production for optimal interferon-γ costimulation in PHA-stimulated cocultures, familial patient interferon-γ production was low and unaffected by their blockade. CD86 blockade caused a greater than 50% reduction in both normal and familial patient interferon-γ production, implying that a majority of residual familial patient costimulation required this pathway. Furthermore, selected myelomonocytic cell lines (K562 and THP1) acted as potent accessory cells for interferon-γ production by familial patient and normal T cells, largely independent of IL-12 production. However, CD86 blockade of K562 cell/familial cell cocultures resulted in less than a 20% reduction in interferon-γ production, indicating that familial patient cells respond to IL-12- and CD86-independent costimulatory signals for interferon-γ as well. Thus, we demonstrate that the familial defect also involves interferon-γ costimulation pathways requiring both CD40/CD40L interaction and IL-12 production, while residual pathways remain that allow low-level interferon-γ production. FamilialMycobacterium aviumpatient monocytes and certain myelomonocytic cell lines can be exploited to investigate IL-12-independent costimulation for interferon-γ production.