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Blood, 1 March 2006, Vol. 107, No. 5, pp. 2004-2012.
Prepublished online as a Blood First Edition Paper on November 3, 2005; DOI 10.1182/blood-2005-06-2345.
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Submitted June 16, 2005
Accepted October 17, 2005
CD4/CD8 double-positive macrophages infiltrating at inflammatory sites: a population of monocytes/macrophages with a cytotoxic phenotype
Tomohisa Baba, Akihiro Ishizu*, Sari Iwasaki, Akira Suzuki, Utano Tomaru, Hitoshi Ikeda, Takashi Yoshiki, and Masanori Kasahara
Department of Pathology/Pathophysiology, Division of Pathophysiological Science, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
* Corresponding author; email: aishizu{at}med.hokudai.ac.jp.
We found a population of nonlymphoid cells expressing both CD4 and CD8 in PBMCs of human T cell leukemia virus type-I pX transgenic rats with autoimmune diseases. These cells, which showed a monocytic phenotype, were found also in wild-type rats, and their number increased by adjuvant-assisted immunization. GM-CSF increased the number of these cells in PBMCs. Consistent with the idea that CD4/CD8 double-positive (DP) monocytes differentiate into DP macrophages at sites of inflammation, we found infiltration of DP macrophages at the site of myosin-induced myocarditis in wild-type rats; these cells exhibited a 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 DP macrophages. DP monocytes had a cytotoxic phenotype similar to DP macrophages, indicating that this phenotypic specialization occurred before entry into a tissue. In line with this, CD4/CD8 DP monocytes killed tumor cells in vitro. Combined evidence indicates that certain inflammatory stimuli that induce GM-CSF trigger the expansion of a population of CD4/CD8 DP monocytes with a cytotoxic phenotype, and that these cells differentiate into macrophages at inflammatory sites. Interestingly, human PBMCs also contain CD4/CD8 DP monocytes.
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