Differential Expression of VEGF Receptors on Human T Cell Subsets

Vascular endothelial growth factors (VEGF) and their receptors (VEGFR) deliver important signals that controlling the angiogenesis of growing, injured, and malignant tissues. Expression of VEGF receptors has been described on a variety of normal and malignant leukocytes, and presumably plays a role in their trafficking to injured tissue. Differential expression of neuropilin-1 (NRP-1) has been described as a marker of regulatory T cells (Treg) in mice, and may be expressed on human thymocytes, but expression on human Tregs has not been confirmed. Moreover, earlier reports of Treg-specific markers in humans were based on the CD4+CD25+ subset, which is not as reliable for Treg identification as it is in mice. We used cell sorting to obtain pure populations of human Tregs (using the more stringent criteria of CD4+CD25+CD125−) and T helper cells (Th) (CD4+CD25−CD127+). We compared expression in these subsets of VEGFR-1, -2, -3, and NRP-1 and -2 using flow cytometry and quantitative RT-PCR, and NRP-1 splice isoforms by RT-PCR using isoform-specific primers. We were not able to identify any NRP-1 expression in Tregs by any of these methods. In contrast, there was marked differential expression of VEGFR-2 (Flk-1) and -3 (Flt-4), both of which exhibited up to 16-fold higher expression in Tregs than in Th. These findings suggest a role for VEGF in recruiting Tregs to sites of tissue growth as a mechanism for blunting potential autoimmunity to neoexpressed antigens, and thus may also explain the accumulation of Tregs in tumors.