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      Engagement of NKG2D on Bystander Memory CD8 T Cells Promotes Increased Immunopathology following Leishmania major Infection

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          Abstract

          One of the hallmarks of adaptive immunity is the development of a long-term pathogen specific memory response. While persistent memory T cells certainly impact the immune response during a secondary challenge, their role in unrelated infections is less clear. To address this issue, we utilized lymphocytic choriomeningitis virus (LCMV) and Listeria monocytogenes immune mice to investigate whether bystander memory T cells influence Leishmania major infection. Despite similar parasite burdens, LCMV and Listeria immune mice exhibited a significant increase in leishmanial lesion size compared to mice infected with L. major alone. This increased lesion size was due to a severe inflammatory response, consisting not only of monocytes and neutrophils, but also significantly more CD8 T cells. Many of the CD8 T cells were LCMV specific and expressed gzmB and NKG2D, but unexpectedly expressed very little IFN-γ. Moreover, if CD8 T cells were depleted in LCMV immune mice prior to challenge with L. major, the increase in lesion size was lost. Strikingly, treating with NKG2D blocking antibodies abrogated the increased immunopathology observed in LCMV immune mice, showing that NKG2D engagement on LCMV specific memory CD8 T cells was required for the observed phenotype. These results indicate that bystander memory CD8 T cells can participate in an unrelated immune response and induce immunopathology through an NKG2D dependent mechanism without providing increased protection.

          Author Summary

          Cutaneous leishmaniasis has a wide spectrum of clinical presentations, from mild self-healing lesions to severe chronic infections. Differences in each individual's response are related to pathogen dose and the genetic and physiological status of the host, but exactly what causes the broad spectrum of disease is not well understood. Here we show that previous infection with a viral or bacterial pathogen led to increased immunopathology associated with L. major infection. This increase in immunopathology was not associated with any changes in parasite control and was characterized by an exaggerated inflammatory infiltrate into the site of infection. Ultimately, this increase in immunopathology was dependent on the presence of memory CD8 T cells from the previous infection and their expression of the NK cell receptor NKG2D, as depletion of these cells prior to infection with L. major or blockade of this receptor during infection ameliorated the disease. Our work suggests that the immunological history of a patient may be playing an underlying role in the pathology associated with leishmania infection and could be an important consideration for the understanding and treatment of this and other human diseases. This work also identifies the NKG2D pathway as a potential new target for therapeutic intervention.

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          Most cited references63

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          Lineage relationship and protective immunity of memory CD8 T cell subsets.

          Memory CD8 T cells can be divided into two subsets, central (T(CM)) and effector (T(EM)), but their lineage relationships and their ability to persist and confer protective immunity are not well understood. Our results show that T(CM) have a greater capacity than T(EM) to persist in vivo and are more efficient in mediating protective immunity because of their increased proliferative potential. We also demonstrate that, following antigen clearance, T(EM) convert to T(CM) and that the duration of this differentiation is programmed within the first week after immunization. We propose that T(CM) and T(EM) do not necessarily represent distinct subsets, but are part of a continuum in a linear naive --> effector --> T(EM) --> T(CM) differentiation pathway.
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            Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease.

            A major function of NKG2D linking innate and adaptive immunity is to upregulate antigen-specific CTL-mediated cytotoxicity in tissues expressing stress-induced NKG2D ligands, such as MIC, by coactivating TCR signaling. Here, we show that, under conditions of dysregulated IL15 expression in vivo in patients with celiac disease and in vitro in healthy individuals, multiple steps of the NKG2D/DAP10 signaling pathway leading to ERK and JNK activation are coordinately primed to activate direct cytolytic function independent of TCR specificity in effector CD8 T cells. These findings may not only explain previous reports of transformation of CTL into NK-like "lymphokine-activated killers" (LAK cells) under high doses of IL2 (a substitute for IL15) but may also have significant implications for understanding and treating immunopathological diseases.
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              Lymphocyte homing and homeostasis.

              The integration and control of systemic immune responses depends on the regulated trafficking of lymphocytes. This lymphocyte "homing" process disperses the immunologic repertoire, directs lymphocyte subsets to the specialized microenvironments that control their differentiation and regulate their survival, and targets immune effector cells to sites of antigenic or microbial invasion. Recent advances reveal that the exquisite specificity of lymphocyte homing is determined by combinatorial "decision processes" involving multistep sequential engagement of adhesion and signaling receptors. These homing-related interactions are seamlessly integrated into the overall interaction of the lymphocyte with its environment and participate directly in the control of lymphocyte function, life-span, and population dynamics. In this article a review of the molecular basis of lymphocyte homing is presented, and mechanisms by which homing physiology regulated the homeostasis of immunologic resources are proposed.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                February 2014
                27 February 2014
                : 10
                : 2
                : e1003970
                Affiliations
                [1 ]Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
                [2 ]Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
                National Institute of Health, United States of America
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: EJC EJW PS. Performed the experiments: EJC. Analyzed the data: EJC MHG. Contributed reagents/materials/analysis tools: EJW PS. Wrote the paper: EJC PS.

                Article
                PPATHOGENS-D-13-01933
                10.1371/journal.ppat.1003970
                3937277
                24586170
                c0ba10d2-86ca-4c94-aa43-73479dab976e
                Copyright @ 2014

                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
                : 18 July 2013
                : 17 January 2014
                Page count
                Pages: 14
                Funding
                This work was supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health grants RO1 A135914 (to PS), U19 AI083022 (to EJW), and U19 AI082630 (to EJW). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Immunology
                Immune cells
                T cells
                Immunity
                Immunity to infections
                Immunopathology
                Medicine
                Infectious diseases
                Neglected tropical diseases
                Leishmaniasis
                Parasitic diseases
                Leishmaniasis
                Viral diseases
                Lymphocytic choriomeningitis
                Bacterial diseases

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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