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      CD103 Deficiency Prevents Graft-versus-Host Disease but Spares Graft-versus-Tumor Effects Mediated by Alloreactive CD8 T Cells

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          Abstract

          Background

          Graft-versus-host disease (GVHD) remains the main barrier to broader application of allogeneic hematopoietic stem cell transplantation (alloSCT) as a curative therapy for host malignancy. GVHD is mediated by allogeneic T cells directed against histocompatibility antigens expressed by host tissues. Based on previous studies, we postulated that the integrin CD103 is required for CD8-mediated GVHD, but not for graft-versus-tumor effects (GVT).

          Methodology/Principal Findings

          We herein provide evidence in support of this hypothesis. To circumvent the potentially confounding influence of donor CD4 T cells, we developed an alloSCT model in which GVHD mortality is mediated by purified CD8 T cells. In this model, host-reactive CD8 T cells receive CD4 T cell help at the time of initial activation but not in the effector phase in which mature CD8 T effectors migrate into host tissues. We show that donor CD8 T cells from wild-type BALB/c mice primed to host alloantigens induce GVHD pathology and eliminate tumors of host origin in the absence of host CD4 T cells. Importantly, CD103 deficiency dramatically attenuated GVHD mortality, but had no detectable impact on the capacity to eliminate a tumor line of host origin. We provide evidence that CD103 is required for accumulation of donor CD8 T cells in the host intestinal epithelium but not in the tumor or host lymphoid compartments. Consistent with these data, CD103 was preferentially expressed by CD8 T cells infiltrating the host intestinal epithelium but not by those infiltrating the tumor, lamina propria, or lymphoid compartments. We further demonstrate that CD103 expression is not required for classic CD8 effector activities including cytokine production and cytotoxicity.

          Conclusions/Significance

          These data indicate that CD103 deficiency inhibits GVHD pathology while sparing anti-tumor effects mediated by CD8 T cells, identifying CD103 blockade as an improved strategy for GVHD prophylaxis.

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          Most cited references18

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          Graft-versus-host disease.

          Haemopoietic-cell transplantation (HCT) is an intensive therapy used to treat high-risk haematological malignant disorders and other life-threatening haematological and genetic diseases. The main complication of HCT is graft-versus-host disease (GVHD), an immunological disorder that affects many organ systems, including the gastrointestinal tract, liver, skin, and lungs. The number of patients with this complication continues to grow, and many return home from transplant centres after HCT requiring continued treatment with immunosuppressive drugs that increases their risks for serious infections and other complications. In this Seminar, we review our understanding of the risk factors and causes of GHVD, the cellular and cytokine networks implicated in its pathophysiology, and current strategies to prevent and treat the disease. We also summarise supportive-care measures that are essential for management of this medically fragile population.
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            Cadherins in cancer: implications for invasion and metastasis.

            M Takeichi (1993)
            In order to understand the mechanisms of metastasis, one must first determine how cancer cells detach from primary tumors. It is known that cadherins are major cell-cell adhesion molecules in tumors as well as in normal tissues. The perturbation of cadherin function causes temporal or permanent disaggregation of tumor cells and may thus promote the invasion and metastasis of such cells.
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              TGF-β–dependent CD103 expression by CD8+ T cells promotes selective destruction of the host intestinal epithelium during graft-versus-host disease

              Destruction of the host intestinal epithelium by donor effector T cell populations is a hallmark of graft-versus-host disease (GVHD), but the underlying mechanisms remain obscure. We demonstrate that CD8+ T cells expressing CD103, an integrin conferring specificity for the epithelial ligand E-cadherin, play a critical role in this process. A TCR transgenic GVHD model was used to demonstrate that CD103 is selectively expressed by host-specific CD8+ T cell effector populations (CD8 effectors) that accumulate in the host intestinal epithelium during GVHD. Although host-specific CD8 effectors infiltrated a wide range of host compartments, only those infiltrating the intestinal epithelium expressed CD103. Host-specific CD8 effectors expressing a TGF-β dominant negative type II receptor were defective in CD103 expression on entry into the intestinal epithelium, which indicates local TGF-β activity as a critical regulating factor. Host-specific CD8 effectors deficient in CD103 expression successfully migrated into the host intestinal epithelium but were retained at this site much less efficiently than wild-type host-specific CD8 effectors. The relevance of these events to GVHD pathogenesis is supported by the finding that CD103-deficient CD8+ T cells were strikingly defective in transferring intestinal GVHD pathology and mortality. Collectively, these data document a pivotal role for TGF-β–dependent CD103 expression in dictating the gut tropism, and hence the destructive potential, of CD8+ T cells during GVHD pathogenesis.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2011
                14 July 2011
                : 6
                : 7
                : e21968
                Affiliations
                [1 ]Department of Surgery, The Ohio State University, Columbus, Ohio, United States of America
                [2 ]Department of Microbiology and Immunology, University of Maryland Medical School, Baltimore, Maryland, United States of America
                [3 ]Department of Pathology, The Ohio State University, Columbus, Ohio, United States of America
                [4 ]Department of Hematology and Oncology, West Virginia University, Morgantown, West Virginia, United States of America
                [5 ]Department of Hematology and Oncology, Arthur G. James Comprehensive Cancer, The Ohio State University, Columbus, Ohio, United States of America
                Saint Louis University, United States of America
                Author notes

                Conceived and designed the experiments: KL GH. Performed the experiments: BA KL AG JW. Analyzed the data: KL GH. Contributed reagents/materials/analysis tools: MY. Wrote the paper: BA KL MH SD GH.

                Article
                PONE-D-11-02696
                10.1371/journal.pone.0021968
                3136479
                21779359
                555c3ef7-72ad-4d9c-932c-b5d038b91ffd
                Liu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 7 February 2011
                : 14 June 2011
                Page count
                Pages: 8
                Categories
                Research Article
                Biology
                Anatomy and Physiology
                Immune Physiology
                Immune Cells
                Immunology
                Immune Cells
                T Cells
                Immunologic Techniques
                Immunohistochemical Analysis
                Immune System
                Immunopathology
                Molecular Cell Biology
                Cellular Types
                Immune Cells
                Medicine
                Anatomy and Physiology
                Immune Physiology
                Immune Cells
                Clinical Immunology
                Immune Cells
                T Cells
                Immunopathology
                Hematology
                Bone Marrow and Stem Cell Transplantation

                Uncategorized
                Uncategorized

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