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      Virtual memory T cells develop and mediate bystander protective immunity in an IL-15-dependent manner

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          Abstract

          Virtual memory cells (VM) are an antigen-specific, memory phenotype CD8 T-cell subset found in lymphoreplete, unchallenged mice. Previous studies indicated that VM cells were the result of homeostatic proliferation (HP) resembling the proliferation observed in a lymphopenic environment. Here we demonstrate that HP is ongoing in lymphoreplete mice, the degree of which is dictated by the number of naive CD8 T cells with a sufficiently high affinity for self-antigen interacting with peripheral IL-15. VM cell transcriptional profiles suggest a capacity to mediate protective immunity via antigen non-specific bystander killing, a function we show is dependent on IL-15. Finally, we show a VM-like population of human cells that accumulate with age and traffic to the liver, displaying phenotypic and functional attributes consistent with the bystander protective functions of VM cells identified in the mouse. These data identify developmental and functional attributes of VM cells, including their likely role in protective immunity.

          Abstract

          Virtual memory T cells are CD8 T cells with memory phenotype present in unimmunized mice. Here the authors show that these cells have higher affinity for self-antigen, depend on IL-15 for proliferation and antigen-non-specific cytotoxicity in mice, and that a similar population exists in humans.

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          Most cited references36

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          Proliferation and differentiation potential of human CD8+ memory T-cell subsets in response to antigen or homeostatic cytokines.

          Four human CD8+ T-cell subsets, naive (CCR7+CD45RA+), central memory (TCM, CCR7+CD45RA-), effector memory (TEM, CCR7-CD45RA-), and CD45RA+ effector memory cells (TEMRA, CCR7-CD45RA+) were compared for their capacity to proliferate and differentiate in response to antigen or homeostatic cytokines. Cytokine responsiveness and interleukin-15 receptor expression were low in naive T cells and progressively increased from TCM to TEM and TEMRA. In contrast, the capacity to accumulate in response to T-cell receptor (TCR) or cytokine stimulation showed a reciprocal pattern and was associated with resistance to cell death and Bcl-2 expression. Whereas all TCR-stimulated cells acquired a CD45RA-CCR7- phenotype, cytokine-stimulated cells maintained their phenotype with the exception of TCM cells, which expressed CCR7, CD45RA, and perforin in various combinations. Single CD8+ TCM cells, but not TEM cells, could be expanded with cytokines, and the obtained clones displayed several distinct phenotypes, suggesting that TCM cells are heterogeneous. Consistently, CCR4 expression in the CD8+ TCM pool discriminated CCR4+ type 2 polarized cells (Tc2) and CCR4-CTL precursors. Finally, ex vivo bromodeoxyuridine (BrdU) incorporation experiments revealed that memory subsets have different in vivo proliferation rates, with CCR4-TCM having the highest turnover and TEMRA the lowest. These results show that human CD8+ memory T-cell subsets have different proliferation and differentiation potentials in vitro and in vivo. Furthermore, they suggest that TEMRA cells are generated from a TCM subset upon homeostatic proliferation in the absence of antigen.
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            Persistence of memory CD8 T cells in MHC class I-deficient mice.

            An understanding of how T cell memory is maintained is crucial for the rational design of vaccines. Memory T cells were shown to persist indefinitely in major histocompatibility complex (MHC) class I-deficient mice and retained the ability to make rapid cytokine responses upon reencounter with antigen. In addition, memory CD8 T cells, unlike naïve cells, divided without MHC-T cell receptor interactions. This "homeostatic" proliferation is likely to be important in maintaining memory T cell numbers in the periphery. Thus, after naïve CD8 T cells differentiate into memory cells, they evolve an MHC class I-independent "life-style" and do not require further stimulation with specific or cross-reactive antigen for their maintenance.
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              T cell-positive selection uses self-ligand binding strength to optimize repertoire recognition of foreign antigens.

              Developing T cells express diverse antigen receptors whose specificities are not prematched to the foreign antigens they eventually encounter. Past experiments have revealed that thymocytes must productively signal in response to self antigens to mature and enter the peripheral T cell pool (positive selection), but how this process enhances effective mature T cell responses to foreign antigen is not fully understood. Here we have documented an unsuspected connection between thymic recognition events and foreign antigen-driven T cell responses. We find that the strength of self-reactivity is a clone-specific property unexpectedly directly related to the strength of T cell receptor (TCR) binding to presented foreign antigen. T cells with receptors showing stronger interaction with self dominate in responses to infections and accumulate in aging individuals, revealing that positive selection contributes to effective immunity by skewing the mature TCR repertoire toward highly effective recognition of pathogens that pose a danger to the host. Copyright © 2013 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group
                2041-1723
                21 April 2016
                2016
                : 7
                : 11291
                Affiliations
                [1 ]Department of Immunology and Microbiology, University of Colorado Denver at Anschutz Medical Campus, School of Medicine , Aurora, Colorado 80045, USA
                [2 ]Department of Medicine and Division of Gastroenterology and Hepatology, University of Colorado Denver at Anschutz Medical Campus, School of Medicine , Aurora, Colorado 80045, USA
                [3 ]Department of Biomedical Research, National Jewish Health , Denver, Colorado 80206, USA
                [4 ]Department of Surgery, University of Colorado Denver at Anschutz Medical Campus, School of Medicine , Aurora, Colorado 80045, USA
                Author notes
                Author information
                http://orcid.org/0000-0002-3861-8602
                Article
                ncomms11291
                10.1038/ncomms11291
                4844673
                27097762
                c3f0ed54-2c90-4eed-a256-b6531c746265
                Copyright © 2016, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 13 October 2015
                : 09 March 2016
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