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

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Naive and Memory T Cells Induce Different Types of Graft-Versus-Host Disease1 The Journal of Immunology 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 Strober2* 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 CD62LhighCD44low) T cells and CD4؉ effector memory (CD62LlowCD44high) 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. Never- theless, 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 Journal of Immunology, 2007, 179: 6547–6554. raft-vs-host disease (GVHD)3 is a major complication of selectin), and the T cell activation molecule, CD44 (10). Naive T allogeneic hemopoietic cell transplantation that is cells express the CD62Lhigh CD44low phenotype, whereas the ef- G caused by mature donor T cells contained in the graft fector memory T cells express the CD62LlowCD44high phenotype from untreated normal donors (1). The contribution of different (10, 11). The differences in the patterns of receptor expression are subsets of donor T cells to the pathogenesis of GVHD has been due to the down-regulation of CD62L and the up-regulation of ϩ studied extensively. Donor CD4 T cells induce injurious immune CD44 on the naive T cell surface after antigenic exposure (10, 11). responses to alloantigens presented by MHC class II molecules on In normal untreated mice, it is thought that CD4ϩ and CD8ϩ T ϩ host APCs, and donor CD8 T cells induces injurious responses to cells with the effector memory phenotype are derived from naive alloantigens presented by MHC class I molecules (2, 3). Donor T cells that have been exposed to environmental Ags (12, 13) or by ϩ ϩ CD4 and CD8 T cell responses may predominate in mouse homeostatic proliferation of naive CD4ϩ T cells (14). It is not clear models of GVHD depending on the donor and host strain combi- whether environmental Ags in the mouse cross-react with mouse nations involving major and/or minor histocompatibility Ag dif- MHC and/or minor histocompatibility Ags. ferences (2). Subsets of naturally occurring regulatory T cells con- Although highly purified naive T cells from untreated normal tained in the graft, such as NK T cells and CD4ϩCD25ϩ T cells, ϩ ϩ donors induced acute lethal GVHD, purified effector memory T suppress GVHD induced by CD4 and CD8 T cells (4, 5). cells from the same donors failed to induce GVHD in irradiated The role of naive and effector memory donor T cell subsets in MHC-mismatched or matched murine hosts used for investigation the induction of GVHD has been studied recently using untreated (6–9). The failure of the latter subset to induce GVHD may reflect normal donor mice (6–9). These subsets can be separated accord- important differences in the biology of naive and effector memory ing to the expression of the cell-trafficking molecule CD62L (L- T cells, or may instead reflect the lack of cross-reactivity between environmental Ags and host histocompatibility Ags. In the absence of cross-reactivity, effector memory T cells from untreated normal do- *Department of Medicine, †Department of Pathology, and ‡Department of Compar- ative Medicine, Stanford University School of Medicine, Stanford University, Stan- nors would be directed to “third-party Ags” and would fail to specif- ford, CA 94305 ically recognize host alloantigens unless the donors had been primed Received for publication June 21, 2007. Accepted for publication September to the alloantigens. In a previous study using an MHC-matched 10, 2007. model, effector memory donor CD4ϩ T cells isolated from mice un- 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 dergoing chronic GVHD induced potent GVHD in secondary recip- with 18 U.S.C. Section 1734 solely to indicate this fact. ients (15). However, the potency of primed effector memory cells an 1 This work was supported by grants from the National Institutes of Health (HL- unprimed effector memory cells was not compared, nor was the dis- 58250, HL-57743, and CA-49604) and a Stanford Vice Provost for Undergraduate tribution and kinetics of tissue injury induced by primed CD4ϩ mem- Education Faculty Grant. ϩ ory T cells compared with purified donor CD4 naive T cells. Naive 2 Address correspondence and reprint requests to Dr. Samuel Strober, Stanford Uni- ϩ versity School of Medicine, Center for Clinical Sciences Research Building, Room CD4 T cells failed to induce lethal GVHD in the dose range 2215-C, 300 Pasteur Drive, Stanford, CA 94305-5166. E-mail address: tested in the MHC-matched strain combination chosen for the [email protected] latter study (15). Thus, the CD4ϩ T memory cells were con- 3 Abbreviations used in this paper: GVHD, graft-vs-host disease; TCD, T cell de- siderably more potent than naive CD4ϩ cells (15). pleted; BM, bone marrow; LP, lamina propria. To make a direct comparison of naive and memory T cells in a Copyright © 2007 by The American Association of Immunologists, Inc. 0022-1767/07/$2.00 setting in which naive T cells induce vigorous GVHD, we studied www.jimmunol.org 6548 MEMORY T CELLS INDUCE GVHD ϩ the ability of purified naive and effector memory CD4 T cells indicated in the text and figures. Mice were kept on antibiotic water (25 from untreated C57BL/6 (H-2b) donors and from C57BL/6 donors ␮g/ml neomycin/0.3 U/ml polymyxin B; Sigma-Aldrich) for the first 28 primed to BALB/c (H-2d) alloantigens for their capacity to induce days. Survival and the signs of GVHD, hair loss, hunched back, swollen faces, and diarrhea were monitored daily and body weight was measured lethal GVHD in MHC-mismatched irradiated BALB/c hosts. We weekly. have previously shown that acute lethal GVHD induced by CD4ϩ T cells in this strain combination is associated with acute colitis Histopathology and pathologic scoring for GVHD severity ϩ that is dependent upon early migration of the CD4 T cells to the Histopathological specimens from the liver and large intestines of hosts mesenteric lymph nodes facilitated by the cell trafficking mole- were obtained at 7 and 72 days after transplantation and fixed in formalin ␣ ␤ before embedding into paraffin blocks. Tissue sections of 4- to 5-␮m thick- cules CD62L and 4 7 integrin (16). Subsequently, the donor ϩ ness were stained with H&E. Microscopic images were obtained using an CD4 T cells migrate to the colon, and induce severe injury to Eclipse E1000M microscope (Nikon) with SPOT RT digital camera and the colonic crypts, associated with diarrhea and death. acquisition software (Diagnostic Instruments) with a final magnification of In the current study, we found that CD4ϩ effector memory T ϫ300 for all images. Image processing was performed with Photoshop CS cells from unprimed donors failed to induce lethal GVHD, but that (Adobe) with standard adjustments of brightness, contrast, and color bal- ance to the entire image. Histologic assessment of liver and colonic GVHD the same cell subset from host alloantigen-primed donors induced was performed in a blinded fashion using the histopathological scoring uniformly lethal GVHD. Surprisingly, the naive T cells induced a system described by Kaplan et al. (17). The mean GVHD score represents more severe and rapid type of GVHD with acute colitis than the the mean Ϯ SD among five animals per group. primed memory T cells. Cell distribution studies Materials and Methods Cell preparation and acute GVHD induction were performed as described above. For day 6 analysis, lymphocytes from tissues of individual mice Animals were used for flow cytometric analysis. Single-cell suspensions from mes- Wild-type C57BL/6 (H-2b) male mice, 5–8 wk old, and male BALB/c enteric lymph nodes, peripheral lymph nodes (bilateral axillary and ingui- (H-2d) mice, 5–10 wk old, were purchased from the breeding facility of the nal nodes were pooled), and spleen were filtered through fine nitex mem- Department of Comparative Medicine (Stanford University, Stanford, CA). branes to remove aggregates. Mononuclear cells from the liver were All mice were housed in a specific pathogen-free facility. Care of all isolated according to the method by Lan et al. (18). Lamina propria (LP) experimental animals was in accordance with institutional and National lymphocytes were purified as described (19). Institutes of Health guidelines. Cytokine assay Abs and FACS Cytokine production after 60 h of allogeneic stimulation was assessed in supernatants of cultures of sorted naive and effector memory CD4ϩ T(1ϫ The following reagents were used for flow cytometric analysis: unconju- 5 gated anti-CD16/32 (2.4G2), anti-CD4 FITC (RM4-5), anti-TCR-␤ allo- 10 cells) from primed and unprimed C57BL/6 donors as responders and irradiated (3000 cGy) Thy1.2-depleted BALB/c splenocytes as allogeneic phycocyanin (H57-597), anti-CD62L allophycocyanin, anti-CD62L biotin 5 ␣ ␤ stimulator cells (5 ϫ 10 cells).
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