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Harvard Medical School, Transplant Research Center, Beth Israel Deaconess Medical Center, Boston, MA 02115
T cell depletion is a widely used approach in clinical transplantation. However, not all T cells are equally sensitive to depletion therapies and a significant fraction of T cells persists even after aggressive treatment. The functional attributes of such T cells and the mechanisms responsible for their resistance to depletion are poorly studied. In the present study, we showed that CD4+ T cells that are resistant to polyclonal anti-lymphocyte serum (ALS) mediated depletion exhibit phenotypic features of memory cells and uniformly express OX40 on the cell surface. Studies using the foxp3gfp knockin mice revealed that the remaining CD4+OX40+ cells consist of Foxp3+ Tregs and Foxp3– T effector/memory cells. The ALS-resistant CD4+OX40+ cells failed to mediate skin allograft rejection upon adoptive transferring into congenic Rag–/– mice, but removal of Foxp3+ Tregs from the OX40+ cells resulted in prompt skin allograft rejection. Importantly, OX40 is critical to survival of both Foxp3+ Tregs and T effector/memory cells. However, OX40 exhibits opposing effects on the functional status of Foxp3+ Tregs and T effector/memory cells, as stimulation of OX40 on T effector cells induced amplified cell proliferation but stimulation of OX40 on the Foxp3+ Tregs impaired their suppressor functions. Our study demonstrates that OX40 is a critical molecule in regulating survival and functions of depletion-resistant T cells; and these findings may have important clinical implications.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the National Institutes of Health (to T.M. and X.C.L.) and the Juvenile Diabetic Research Foundation International (to X.C.L.).
2 Address correspondence and reprint requests to Dr. Xian C. Li, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, HIM-1025, Boston, MA 02215. E-mail address: xli{at}bidmc.harvard.edu
3 Abbreviations used in this paper: ALS, anti-lymphocyte serum; ATG, anti-thymoglobulin; KI, knockin; wt, wild type.
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