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Homeostatic Proliferation of Lymphocytes Results in Augmented Memory-Like Function and Accelerated Allograft Rejection¹

Victoria F. Moxham^*, Julieta Karegli^*, Richard E. Phillips^*, Kathryn L. Brown^*, Thomas T. Tapmeier^*, Robert Hangartner, Steven H. Sacks^* and Wilson Wong^2,*

^* Department of Nephrology and Transplantation and Department of Histopathology, King’s College London School of Medicine at Guy’s, King’s and St. Thomas’ Hospital, London, United Kingdom

Homeostatic proliferation is a normal physiological process triggered by lymphopenia to maintain a constant level of T cells. It becomes the predominant source of new T cells in adulthood after thymus regression. T cells that have undergone homeostatic proliferation acquire the memory phenotype, cause autoimmune disease, and are resistant to tolerance induction protocols. Transplantation is a rare example in which lymphopenia is deliberately induced for its immunosuppressive effect. However, it is not known whether the homeostatic proliferation that follows will have the opposite effect and accelerate rejection. We show that T cells that have undergone homeostatic proliferation acquire a memory phenotype, spontaneously skews toward the Th1 phenotype, even in the absence of antigenic stimulus. Interestingly, in contrast, the percentage of Foxp3⁺ regulatory T cells increased by 28-fold following homeostatic proliferation. Using a mouse life-sustaining kidney transplant model, we showed that T cells that have gone through homeostatic proliferation in lymphopenic hosts transformed chronic rejection to acute rejection of a single MHC class II-mismatched kidney allograft. T cells that have undergone homeostatic proliferation consistently cause reliable rejection even when bona fide memory T cells cannot. These functional changes are long-lasting and not restricted to the acute phase of homeostatic proliferation. Our findings have important implications for tolerance induction or graft-prolonging protocols involving leukocyte depletion such as irradiation bone marrow chimera, T cell-depleting Abs, and lymphopenia induced by infections such as CMV and HIV.

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 Kidney Research U.K., the Wingate Foundation, and British Transplantation Society.

² Address correspondence and reprint requests to Dr. Wilson Wong, Department of Nephrology and Transplantation, Guy’s Hospital, London, SE1 9RT, U.K. E-mail address: wilson.wong{at}kcl.ac.uk

³ Abbreviations used in this paper: WT, wild type; HPF, high-power field; MST, median survival time; BL/6, C57BL6.