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Naive and Memory T Cells Induce Different Types of Graft-versus-Host Disease¹

Suparna Dutt^*, Diane Tseng^*, Joerg Ermann^*, Tracy I. George, Yin Ping Liu^*, Corrine R. Davis, C. Garrison Fathman^* and Samuel Strober^2,*

^* Department of Medicine, Department of Pathology, and Department of Comparative Medicine, Stanford University School of Medicine, Stanford University, Stanford, CA 94305

The goal of this study was to compare the ability of donor naive and alloantigen-primed effector memory T cells to induce graft-vs-host disease after bone marrow transplantation in MHC-mismatched irradiated host mice. Purified CD4⁺ naive (CD62L^highCD44^low) T cells and CD4⁺ effector memory (CD62L^lowCD44^high) T cells obtained from unprimed donors and donors primed to host alloantigens, respectively, were injected into host mice, and the rapidity, severity, and pattern of tissue injury of graft-vs-host disease was assessed. Unexpectedly, the naive T cells induced a more acute and severe colitis than the primed memory cells. Whereas the naive T cells expressing CD62L and CCR7 lymph node homing receptors vigorously expanded in mesenteric lymph nodes and colon by day 6 after transplantation, the primed memory T cells without these receptors had 20- to 100-fold lower accumulation at this early time point. These differences were reflected in the significantly more rapid decline in survival and weight loss induced by naive T cells. The primed memory T cells had a greater capacity to induce chronic colitis and liver injury and secrete IL-2 and IFN- in response to alloantigenic stimulation compared with memory T cells from unprimed donors. Nevertheless, the expected increase in potency as compared with naive T cells was not observed due to differences in the pattern and kinetics of tissue injury.

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 grants from the National Institutes of Health (HL-58250, HL-57743, and CA-49604) and a Stanford Vice Provost for Undergraduate Education Faculty Grant.

² Address correspondence and reprint requests to Dr. Samuel Strober, Stanford University School of Medicine, Center for Clinical Sciences Research Building, Room 2215-C, 300 Pasteur Drive, Stanford, CA 94305-5166. E-mail address: sstrober{at}stanford.edu

³ Abbreviations used in this paper: GVHD, graft-vs-host disease; TCD, T cell depleted; BM, bone marrow; LP, lamina propria.