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ThPOK Derepression Is Required for Robust CD8 T cell Responses to Viral Infection^1,2

Ruka Setoguchi^*, Ichiro Taniuchi and Michael J. Bevan^3,*

^* Department of Immunology and the Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195; and Laboratory for Transcriptional Regulation, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan

In the thymus, the transcription factor ThPOK is essential for the development of the CD4 helper T cell lineage, whereas active repression of ThPOK is critical for the development of the CD8 cytotoxic T cell lineage. ThPOK gene silencing is thought to be irreversible in peripheral CD8 T cells. We noticed that ThPOK repression is readily abrogated upon in vitro TCR stimulation of peripheral CD8 T cells. This observation prompted us to investigate a role for ThPOK in the CD8 T cell response to an acute viral infection. We observed that a functional deficiency of ThPOK does not affect CD8 T cell differentiation into effector T cells and the long-term persistence of Ag-specific memory T cells. However, in the absence of functional ThPOK, clonal expansion is significantly less in both primary and secondary CD8 T cell responses. Long-lived, Ag-specific CD8 T cells with a functional deficiency in ThPOK fail to produce high amounts of IL-2 and also fail to express high levels of granzyme B upon rechallenge. Our data reveal an unexpected role for ThPOK in CD8 T cells in promoting expansion and boosting the response to antigenic challenge.

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 (to M.J.B.) and by National Institutes of Health Grant AI19335.

² The microarray data presented in this article have been submitted to the Gene Expression Omnibus under accession numbers GSM426400, GSM426401, GSM426402, and GSM426403.

³ Address correspondence and reprint requests to Dr. Michael J. Bevan, Department of Immunology, University of Washington, Box 357370, 1959 Northeast Pacific Street, Seattle, WA 98195-7650. E-mail address: mbevan{at}u.washington.edu

⁴ Abbreviations used in this paper: HD, helper deficient; Eomes, eomesodermin; LCMV, lymphocytic choriomeningitis virus; GP₃₃, LCMV-derived GP_33–41 epitope; LM, Listeria monocytogenes; MFI, mean fluorescence intensity; WT, wild type.

⁵ The online version of this article contains supplemental material.