A number of cells surface glycoproteins have been referred to as “NK receptors” either for historical reasons (they were first identified on NK cells) or because they are predominantly expressed on NK cells. Included in this “NK receptor” category are members of the Ly49, KIR, CD94, NKG2, 2B4 (CD244), DX5 (CD49b), CD16, CD56, NKR-P1 (CD161), and NK Cytotoxicity Receptor (NCR) families 11. However, all of these “NK receptors” can be expressed on subsets of T cells or other cell types. Although most of these “NK receptors” are not expressed on resting, naïve αβ-TCR+ T cells, they are frequently acquired after activation, predominantly on CD8+ T cells, but also on some CD4+ T cells. By contrast, “NK receptors” are often detected on γδ-TCR+ T cells, even without deliberate activation of these cells. In the present study, Stewart et al.3 detected expression of NK1.1, 2B4, NKG2D, NKG2A, and Ly49 on mouse γδ-TCR+ T cells. In addition, NKp46, which is considered one of the receptors most selectively expressed on NK cells, was found on ∼60% of these NK1.1+ γδ-TCR+ T cells (Fig. 1). These investigators noted an inverse correlation between the cell surface density of the CD3/γδ-TCR complex and NK1.1 (and other “NK receptors”) on this subset; therefore, unless very sensitive methods of detection are used to analyze the expression of CD3 or TCR, these cells might easily be inappropriately identified as NK cells, rather than γδ-TCR+ T cells. A similar problem is encountered when NK1.1+ “NKT cells” expressing the invariant Vα14 TCR are activated – they down-regulate the CD3/TCR complex rendering them essentially indistinguishable from NK cells 12. Studies of the intraepithelial lymphocytes isolated from the small intestine of patients with celiac disease have uncovered oligoclonal populations of αβ-TCR+ CD8+ T cells displaying lower amounts of TCR/CD3 on the cell surface and an abundance of “NK receptors”, suggesting that these cells have been “re-programmed” to acquire receptors enabling them to mediate functions usually mediated by NK cells 13.
Recent studies have also described a minor population of NK1.1+ cells lacking cells surface expression of CD3 in the thymus and spleen of wild-type and TCRβ–/–δ–/– mice that express in-frame rearranged TCRγ genes 14. These cells are absent in nude mice, implying a requirement for the thymus for their development. This minor subset of cells may represent aberrant γδ-T cells that are unable to generate a functional TCRδ chain and persist rather than die. A similar population of thymic-dependent NK1.1+ cells (also expressing NKG2D, CD94, and DX5) has also been described by Vosshenrich and colleagues 15. Whether these cells express in-frame rearranged TCRγ genes was not reported; however, unlike conventional NK cells these thymic-dependent NK1.1+ cells required Gata-3 and IL-7 for their development. This cell type has been proposed as a novel thymic-dependent NK cell subset, but might instead be failed δγ-T cells, whose functional relevance is as yet unknown.