CD4+/CD8+ macrophages infiltrating at inflammatory sites:: a population of monocytes/macrophages with a cytotoxic phenotype

We found a population of nonlymphoid cells expressing both CD4 and CD8 in peripheral blood mononuclear cells (PBMCs) of human T-cell leukemia virus type-I pX transgenic rats with autoimmune diseases. These cells, which showed a monocytic phenotype, were also found in wild-type rats, and their number increased by adjuvant-assisted immunization. GM-CSF increased the number of these double-positive (DIP) monocytes in PBMCs. Consistent with the idea that DIP monocytes differentiate into DIP macrophages at sites of inflammation, we found infiltration of DIP macrophages at the site of myosin-induced myocarditis in wild-type rats; these cells exhibited a T-helper 1 (Th1)-type cytokine/chemokine profile and expressed high levels of Fas ligand, perforin, granzyme B, and NKR-P2 (rat orthologue of human NKG2D). Adoptive transfer of GFP-positive spleen cells confirmed hematogenous origin of DIP macrophages. DIP monocytes had a cytotoxic phenotype similar to DID macrophages, indicating that this phenotypic specialization occurred before entry into a tissue. In line with this, DIP monocytes killed tumor cells in vitro. Combined evidence indicates that certain inflammatory stimuli that induce GM-CSF trigger the expansion of a population of DIP monocytes with a cytotoxic phenotype and that these cells differentiate into macrophages at inflammatory sites. Interestingly, human PBMCs also contain DIP monocytes.