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Published June 25, 2007

ARTICLE

Bim/Bcl-2 balance is critical for maintaining naive and memory T cell homeostasis
Sara Wojciechowski,1 Pulak Tripathi,1 Tristan Bourdeau,1 Luis Acero,2 H. Leighton Grimes,1 Jonathan D. Katz,2 Fred D. Finkelman,1,3 and David A. Hildeman1
1Division 3Division

of Immunobiology and 2Division of Endocrinology, Cincinnati Children’s Hospital, Cincinnati, OH45229 of Immunology, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229

The Journal of Experimental Medicine

We examined the role of the antiapoptotic molecule Bcl-2 in combating the proapoptotic molecule Bim in control of naive and memory T cell homeostasis using Bcl-2−/− mice that were additionally deficient in one or both alleles of Bim. Naive Tcells were significantly decreased in Bim+/−Bcl-2−/− mice, but were largely restored in Bim−/−Bcl-2−/− mice. Similarly, a synthetic Bcl-2 inhibitor killed wild-type, but not Bim−/−, T cells. Further, T cells from Bim+/−Bcl-2−/− mice died rapidly ex vivo and were refractory to cytokine-driven survival in vitro. In vivo, naive CD8+ T cells required Bcl-2 to combat Bim to maintain peripheral survival,whereas naive CD4+ T cells did not. In contrast, Bim+/−Bcl-2−/− mice generated relatively normal numbers of memory T cells after lymphocytic choriomeningitis virus infection. Accumulation of memory T cells in Bim+/−Bcl-2−/− mice was likely caused by their increased proliferative renewal because of the lymphopenic environment of the mice. Collectively, these data demonstrate a critical role for abalance between Bim and Bcl-2 in controlling homeostasis of naive and memory T cells.

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CORRESPONDENCE David A. Hildeman: David.Hildeman@chmcc.org Abbreviations used: LCMV, lymphocytic choriomeningitis virus; pfu, plaque-forming unit; SP, single-positive thymocyte.

Maintenance of T cell homeostasis is critical for normal functioning of theimmune system. After thymocyte selection, T cells enter the periphery, where they are maintained as resting naive cells. Transient disruption of homeostasis occurs when naive T cells undergo antigen-driven expansion and acquire effector functions. Effector T cells then either undergo apoptosis or survive to become memory cells. This process resets T cell homeostasis, promotes protective immunity,and limits autoimmunity. Thus, T cell homeostasis is ultimately achieved through maintenance of distinct T cell populations (naive, effector, and memory), although the mechanisms that maintain homeostasis in each population are not fully understood. Regulation of responsiveness to soluble cytokines and cytokine availability is one mechanism that maintains independent T cell populations. For example,whereas naive T cell homeostasis is mostly intact in the absence of IL-15 (1, 2), IL-15–deficient mice are defective in maintaining memory T cells over time (1–4). This is because the slow proliferative turnover that is crucial for the maintenance of memory, but not
The online version of this article contains supplemental material.

naive, CD8+ T cells in vivo is IL-15–dependent (2–6).Differential responsiveness to IL-15 between naive and memory T cells is at least partly explained by differences in their IL-15R expression (7). IL-7, on the other hand, is critical for maintenance of both naive and memory T cell homeostasis (8, 9, 10–12). IL-7 regulation of molecules that promote or inhibit apoptosis is likely responsible for the effects of IL-7, inasmuch as overexpression of theantiapoptotic molecule Bcl-2 or genetic loss of the proapoptotic molecule Bim largely restores peripheral T cell homeostasis in the absence of IL-7R signaling (13–15). Thus, competition for available IL-7 limits total T cell numbers, whereas IL-15 allows proliferative renewal of memory CD8+ T cells without major effects on the naive T cell pool. Recent experiments have begun to shed light on how...
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