PLoS Pathogens | |
Out-of-Sequence Signal 3 as a Mechanism for Virus-Induced Immune Suppression of CD8 T Cell Responses | |
Raymond M. Welsh1  Stina L. Urban1  | |
[1] Department of Pathology, Immunology and Virology Program, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America | |
关键词: T cells; Cytotoxic T cells; Cytokines; STAT signaling; Phosphorylation; Cell cycle; cell division; Cell staining; Immune suppression; | |
DOI : 10.1371/journal.ppat.1004357 | |
学科分类:生物科学(综合) | |
来源: Public Library of Science | |
【 摘 要 】
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.
【 授权许可】
CC BY
【 预 览 】
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RO201902018492525ZK.pdf | 1974KB | download |