HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kamimura, D. Articles by Bevan, M. J. Search for Related Content PubMed PubMed Citation Articles by Kamimura, D. Articles by Bevan, M. J.

Endoplasmic Reticulum Stress Regulator XBP-1 Contributes to Effector CD8⁺ T Cell Differentiation during Acute Infection¹

Department of Immunology and Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195

The transcription factor X-box-binding protein-1 (XBP-1) plays an essential role in activating the unfolded protein response in the endoplasmic reticulum (ER). Transcribed XBP-1 mRNA is converted to its active form by unconventional cytoplasmic splicing mediated by inositol-requiring enzyme-1 (IRE-1) upon ER stress. We report activation of the IRE-1/XBP-1 pathway in effector CD8⁺ T cells during the response to acute infection. Transcription of unspliced XBP-1 mRNA is up-regulated by IL-2 signals, while its splicing is induced after TCR ligation. Splicing of XBP-1 mRNA was evident during the expansion of Ag-specific CD8⁺ T cells in response to viral or bacterial infection. An XBP-1 splicing reporter revealed that splicing activity was enriched in terminal effector cells expressing high levels of killer cell lectin-like receptor G1 (KLRG1). Overexpression of the spliced form of XBP-1 in CD8⁺ T cells enhanced KLRG1 expression during infection, whereas XBP-1^–/– CD8⁺ T cells or cells expressing a dominant-negative form of XBP-1 showed a decreased proportion of KLRG1^high effector cells. These results suggest that, in the response to pathogen, activation of ER stress sensors and XBP-1 splicing contribute to the differentiation of end-stage effector CD8⁺ T cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Howard Hughes Medical Institute and by Grant AI19335 from the National Institutes of Health (to M.J.B.).

² Address correspondence and reprint requests to Dr. Michael J. Bevan, Department of Immunology, Office I604H Health Science Center, Box 357370, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195-7370. E-mail address: mbevan{at}u.washington.edu

³ Abbreviations used in this paper: KLRG1, killer cell lectin-like receptor G1; ER, endoplasmic reticulum; ERAI, ER stress-activated indicator; ATF, activating transcription factor; eIF2, eukaryotic translation initiation factor 2; IRE-1, inositol-requiring enzyme-1; XBP-1, X-box-binding protein-1; LCMV, lymphocytic choriomeningitis virus; PERK, protein kinase R-like ER kinase; p.i., postinfection; UPR, unfolded protein response; WT, wild type.