In contrast to mice, CD25 deficiency in humans is accompanied by severe immunodeficiency that is characterized by susceptibility to opportunistic pathogens and a normal Treg frequency [9, 14, 15, 21-24]. In addition, IL-2-deficient mice are fully capable of rejecting allografts, whereas CD25-deficient humans are not [24, 49, 50]. Therefore, CD25 may be more important for effector function in humans and more
important for tolerance in mice since only Treg cells constitutively express CD25 in mice. This may explain why blocking CD25 during tumor immuno-therapy has not translated well from mice to humans . Discrepancies between mouse and human immunology selleck have been described elsewhere and is not unexpected since the species diverged 65–75 million years ago . Therefore, studies conducted in mice on the role of IL-2 Seliciclib ic50 in T-cell function may not exactly translate to humans, and this study may offer one possible explanation for these differences.
We believe that the discovery of this CD4+CD25INT population is particularly important for therapies that target CD25/IL-2 and that hopefully by studying the response of this population we can better understand the mechanism of these therapies and improve their clinical efficacy. We evaluated the response of the CD4+CD25INTFOXP3− population to IL-2 immunotherapy. Over the course of IL-2 immunotherapy in cancer patients, the percentage
of CD4+ T cells that were CD25INT population decreased, while the CD25NEG increased and Treg populations stayed relatively stable, Cyclin-dependent kinase 3 suggesting these populations were differentially affected by the therapy. From these studies, it was clear that the CD25INT population was affected by the IL-2 therapy, however, it is currently not known exactly how the CD25INT population responded to the therapy. One possibility is that the CD25INT cells may have downregulated or shed CD25 . However, we did not see diminution of CD25 on the Treg cells, and we demonstrated that not all of the CD25INT population downregulated expression of CD25 in response to rhIL-2 in vitro and that some even increased CD25 expression. In addition, in vitro stimulation with rhIL-2 also suggested that the CD25INT cells are differentially responsive to rhIL-2, as shown by Ki67 staining, and could therefore be act-ivated to a greater degree than the CD25NEG and Treg populations. Therefore, we believe that the disappearance of the CD25INT population observed in IL-2 cancer patients is most likely a combination of events, including decreased surface expression of CD25 and increased activation, which might have led to AICD and/or egress from the blood to tissue. Nevertheless, it is clear that the CD25INT population is greatly affected by IL-2 immunotherapy and may be integral to the antitumor immune response.