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      Non-Hematopoietic Cells in Lymph Nodes Drive Memory CD8 T Cell Inflation during Murine Cytomegalovirus Infection

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          Abstract

          During human and murine cytomegalovirus (MCMV) infection an exceptionally large virus-specific CD8 T cell pool is maintained in the periphery lifelong. This anomalous response is only seen for specific subsets of MCMV-specific CD8 T cells which are referred to as 'inflationary T cells'. How memory CD8 T cell inflation is induced and maintained is unclear, though their activated phenotype strongly suggests an involvement of persistent antigen encounter during MCMV latency. To dissect the cellular and molecular requirements for memory CD8 T cell inflation, we have generated a transgenic mouse expressing an MHC class I-restricted T cell receptor specific for an immunodominant inflationary epitope of MCMV. Through a series of adoptive transfer experiments we found that memory inflation was completely dependent on antigen presentation by non-hematopoietic cells, which are also the predominant site of MCMV latency. In particular, non-hematopoietic cells selectively induced robust proliferation of inflationary CD8 T cells in lymph nodes, where a majority of the inflationary CD8 T cells exhibit a central-memory phenotype, but not in peripheral tissues, where terminally differentiated inflationary T cells accumulate. These results indicate that continuous restimulation of central memory CD8 T cells in the lymph nodes by infected non-hematopoietic cells ensures the maintenance of a functional effector CD8 T pool in the periphery, providing protection against viral reactivation events.

          Author Summary

          Cytomegaloviruses (CMVs) infect the majority of the human population and persist lifelong via latency. CMV latency is thought to be a dynamic state, characterized by stochastic viral reactivation events coupled to CMV-derived antigen presentation. In support of this hypothesis is the exceptionally large CMV-specific CD8 T cell response which constitutes an integral part of immune surveillance of CMV reactivation. Conversely, it may also contribute to immune senescence as it significantly shapes the overall CD8 T cell pool in bias of CMV-specificity. In mice, only a subset of CMV-specific CD8 T cells, also called ‘inflationary CD8 T cells’, contribute to this large response. The mechanism leading to the selective accumulation and persistence of memory CD8 T cells during MCMV latency is largely unknown. Here, we unraveled the mechanisms of memory CD8 T cell inflation using a newly generated TCR transgenic mouse with specificity for an immunodominant inflationary MCMV epitope. We show that antigen presentation on non-hematopoietic cells is essential for memory inflation and that memory inflation in peripheral tissues is fueled by lymph node-resident central memory CD8 T cells, being locally reactivated by non-hematopoietic cells, inducing their local expansion and migration to peripheral tissues where they control viral reactivation events.

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          Most cited references43

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          Phenotypic analysis of antigen-specific T lymphocytes.

          Identification and characterization of antigen-specific T lymphocytes during the course of an immune response is tedious and indirect. To address this problem, the peptide-major histocompatability complex (MHC) ligand for a given population of T cells was multimerized to make soluble peptide-MHC tetramers. Tetramers of human lymphocyte antigen A2 that were complexed with two different human immunodeficiency virus (HIV)-derived peptides or with a peptide derived from influenza A matrix protein bound to peptide-specific cytotoxic T cells in vitro and to T cells from the blood of HIV-infected individuals. In general, tetramer binding correlated well with cytotoxicity assays. This approach should be useful in the analysis of T cells specific for infectious agents, tumors, and autoantigens.
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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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              Molecular and functional profiling of memory CD8 T cell differentiation.

              How and when memory T cells form during an immune response are long-standing questions. To better understand memory CD8 T cell development, a time course of gene expression and functional changes in antigen-specific T cells during viral infection was evaluated. The expression of many genes continued to change after viral clearance in accordance with changes in CD8 T cell functional properties. Even though memory cell precursors were present at the peak of the immune response, these cells did not display hallmark functional traits of memory T cells. However, these cells gradually acquired the memory cell qualities of self-renewal and rapid recall to antigen suggesting the model that antigen-specific CD8 T cells progressively differentiate into memory cells following viral infection.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                October 2011
                October 2011
                27 October 2011
                : 7
                : 10
                : e1002313
                Affiliations
                [1 ]Institute of Microbiology, ETH Zürich, Zürich, Switzerland
                [2 ]Ludwig-Maximilians-University, Munich, Germany
                [3 ]Institute of Laboratory Animal Science and Biomodels Austria, University of Veterinary Medicine Vienna, Vienna, Austria
                Oregon Health Sciences University, United States of America
                Author notes

                Conceived and designed the experiments: NT SMW AO. Performed the experiments: NT. Analyzed the data: NT SMW AO. Contributed reagents/materials/analysis tools: TB TR. Wrote the paper: NT AO.

                Article
                PPATHOGENS-D-11-01136
                10.1371/journal.ppat.1002313
                3203160
                22046127
                85368541-281a-4606-ba0e-381783b3d30c
                Torti 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
                : 31 May 2011
                : 29 August 2011
                Page count
                Pages: 12
                Categories
                Research Article
                Biology
                Immunology
                Immune Cells
                T Cells
                Immunity
                Immunity to Infections
                Immune Response
                Medicine
                Infectious Diseases
                Viral Diseases
                Cytomegalovirus Infection

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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