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      Out-of-Sequence Signal 3 as a Mechanism for Virus-Induced Immune Suppression of CD8 T Cell Responses

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      PLoS Pathogens
      Public Library of Science

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          Abstract

          Virus infections are known to induce a transient state of immune suppression often associated with an inhibition of T cell proliferation in response to mitogen or cognate-antigen stimulation. Recently, virus-induced immune suppression has been linked to responses to type 1 interferon (IFN), a signal 3 cytokine that normally can augment the proliferation and differentiation of T cells exposed to antigen (signal 1) and co-stimulation (signal 2). However, pre-exposure of CD8 T cells to IFN-inducers such as viruses or poly(I∶C) prior to antigen signaling is inhibitory, indicating that the timing of IFN exposure is of essence. We show here that CD8 T cells pretreated with poly(I∶C) down-regulated the IFN receptor, up-regulated suppressor of cytokine signaling 1 (SOCS1), and were refractory to IFNβ-induced signal transducers and activators of transcription (STAT) phosphorylation. When exposed to a viral infection, these CD8 T cells behaved more like 2-signal than 3-signal T cells, showing defects in short lived effector cell differentiation, reduced effector function, delayed cell division, and reduced levels of survival proteins. This suggests that IFN-pretreated CD8 T cells are unable to receive the positive effects that type 1 IFN provides as a signal 3 cytokine when delivered later in the signaling process. This desensitization mechanism may partially explain why vaccines function poorly in virus-infected individuals.

          Author Summary

          Vaccines are used to protect individuals against infection with a number of different pathogens and depend on the formation of antigen specific memory cells. The efficacy of vaccines can be affected by a number of different factors. It has been known for some time now that suppression of the immune system occurs during acute viral infections. Thus, receiving a vaccine during an acute illness may reduce the efficacy of the vaccine administered. We have identified a common mechanism of immune suppression that may occur with many different pathogens that induce a particular inflammatory response. Any pathogen that induces type 1 interferon could potentially suppress the immune response to a subsequent pathological insult. The mechanism of immune suppression identified here was not having a direct negative effect on lymphocytes, but rather was inhibiting the cells ability to receive positive signals that influence their differentiation, expansion and memory formation. This desensitization mechanism may partially explain why vaccines function poorly in virus-infected individuals.

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          Most cited references58

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          Type I interferons act directly on CD8 T cells to allow clonal expansion and memory formation in response to viral infection

          T cell expansion and memory formation are generally more effective when elicited by live organisms than by inactivated vaccines. Elucidation of the underlying mechanisms is important for vaccination and therapeutic strategies. We show that the massive expansion of antigen-specific CD8 T cells that occurs in response to viral infection is critically dependent on the direct action of type I interferons (IFN-Is) on CD8 T cells. By examining the response to infection with lymphocytic choriomeningitis virus using IFN-I receptor–deficient (IFN-IR0) and –sufficient CD8 T cells adoptively transferred into normal IFN-IR wild-type hosts, we show that the lack of direct CD8 T cell contact with IFN-I causes >99% reduction in their capacity to expand and generate memory cells. The diminished expansion of IFN-IR0 CD8 T cells was not caused by a defect in proliferation but by poor survival during the antigen-driven proliferation phase. Thus, IFN-IR signaling in CD8 T cells is critical for the generation of effector and memory cells in response to viral infection.
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            Memory CD8+ T cell differentiation: initial antigen encounter triggers a developmental program in naïve cells.

            The rules that govern memory T cell differentiation are not well understood. This study shows that after antigenic stimulation naïve CD8+ T cells become committed to dividing at least seven times and differentiating into effector and memory cells. Once the parental naïve CD8+ T cell had been activated, this developmental process could not be interrupted and the daughter cells continued to divide and differentiate in the absence of further antigenic stimulation. These data indicate that initial antigen encounter triggers an instructive developmental program that does not require further antigenic stimulation and does not cease until memory CD8+ T cell formation.
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              Naïve CTLs require a single brief period of antigenic stimulation for clonal expansion and differentiation.

              In defense of the host, the immune system must often raise an effective cytotoxic T lymphocyte (CTL) response from a small number of clonal precursors. The degree to which activation stimuli regulate the expansion and differentiation of naïve CTLs, however, remains unknown. Using an engineered antigen-presenting cell (APC) system that allows control over antigenic stimulation, we studied the signaling duration requirements for priming and clonal expansion of naïve CTLs. We found that naïve CTLs become committed after as little as 2 h of exposure to APCs and that their subsequent division and differentiation can occur without the need for further antigenic stimulation of the daughter cells, whether priming is in vitro or in vivo. These data show that after a brief interaction with stimulatory APCs, naïve CTLs initiate a program for their autonomous clonal expansion and development into functional effectors.
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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
                September 2014
                25 September 2014
                : 10
                : 9
                : e1004357
                Affiliations
                [1]Department of Pathology, Immunology and Virology Program, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
                Nationwide Children's Hospital, United States of America
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: SLU RMW. Performed the experiments: SLU. Analyzed the data: SLU RMW. Contributed reagents/materials/analysis tools: RMW. Wrote the paper: SLU RMW.

                Article
                PPATHOGENS-D-14-00260
                10.1371/journal.ppat.1004357
                4177909
                25255454
                6d18c72e-f038-4800-b28c-2dc1358a2996
                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
                : 29 January 2014
                : 28 July 2014
                Page count
                Pages: 17
                Funding
                This work was supported by NIH research grants AI017672, AI081675, AI046629, training grant AI007349, and by UMMS Diabetes and Endocrinology Research Center Grant DK32520. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Immunology
                Medicine and Health Sciences
                Infectious Diseases

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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