Seminars in Immunology 17 (2005) 201–207 Endogenous proliferation: Burst-like CD4 T cell proliferation in lymphopenic settings Booki Min ∗ , William E. Paul Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA Abstract Rapid and slow proliferation is observed when na¨ ıve CD4 T cells are transferred into lymphopenic hosts. We have recently proposed that the rapid, burst-like proliferation, designated endogenous proliferation, is a peripheral mechanism by which memory T cells of diverse specificity are generated without exogenous antigenic stimulation. In this review, we discuss some of unique features of endogenous proliferation. We argue that it is regulated not by the absolute number of memory cells present but by the range of specificities of those cells. We discuss the physiologic significance of endogenous proliferation and outline goals for future studies. Published by Elsevier Ltd. Keywords: CD4 T cells; Endogenous proliferation; Homeostasis; Lymphopenia 1. Introduction Homeostasis: The ability or tendency of an organism or cell to maintain internal equilibrium by adjusting its physiological processes (American Heritage of the American Language). Understanding peripheral T lymphocyte homeostasis has recently become an area of particular interest. The desig- nation “homeostatic proliferation” was used by early au- thors who demonstrated that T cells undergo proliferative re- sponses upon transfer into sublethally irradiated hosts [1,2]. It was proposed that such proliferation was to compensate for the deficit of T cells in the lymphopenic environment. Such proliferation could be of potential importance in patients who are lymphopenic as a result of virus infection, chemotherapy or radiotherapy. Using an experimental system where one transfers T cells into mice with genetically determined or induced lymphope- nia, an understanding of several aspects of homeostatic con- trol of peripheral lymphocytes has been attained. We and others have demonstrated that such homeostatic mechanisms are also operative in the periphery of 1-day old mice resulting ∗ Corresponding author. Tel.: +1 301 496 5046; fax: +1 301 496 0222. E-mail addresses: minb@ccf.org (B. Min), wpaul@niaid.nih.gov (W.E. Paul). in proliferative responses of the first cohorts of thymic emi- grants, implying that lymphopenia-driven T cell proliferation is a physiologic process that has broad biological significance [3–5]. 2. Endogenous proliferation: a physiologic T cell response in lymphopenia When na¨ ıve CD4 T lymphocytes are introduced into a lym- phopenic environment, a subpopulation of the cells begins to proliferate. Some undergo a series of burst-like divisions, 7 or more, within a 1-week period. Associated with these divi- sions, the cells acquire many of the characteristics of mem- ory/effector cells. They become CD44 bright , a portion of them acquire the capacity to produce IFN upon stimulation and many of the cells that have divided multiple times are found in parenchymal tissues such as the liver. This burst-like prolifer- ation of na¨ ıve CD4 T cells occurs even after transfer into TCR transgenic mice, indicating that the endogenous transgenic T cells are not controlling the proliferation of the transferred CD4 T cells and that the absolute number of peripheral T cells is not the principal determinant of this “homeostatic” response [6–8]. In a previous publication [6], we designated this burst-like division as spontaneous proliferation but prefer to refer to it as endogenous proliferation, a term we will use 1044-5323/$ – see front matter. Published by Elsevier Ltd. doi:10.1016/j.smim.2005.02.005