CD8 T cell Responses to Viral Infection ThPOK Derepression Is Required for Robust

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. F ollowing an acute infection, memory CD8 T cells survive and persist for a long period of time after most effector CD8 T cells die upon pathogen clearance. Memory CD8 T cells acquire unique features that distinguish them from naive and effector CD8 T cells (1). The key features of memory CD8 T cells include not only a long life, but also more robust proliferation, more rapid reactivation of cytotoxic molecules, and more rapid production of cytokines than naive T cells after encountering Ag (2–5). Memory CD8 T cells express higher CD127 expression levels and produce higher amount of IL-2 than effector CD8 T cells; however, they lose those features during the secondary response (6, 7). Unknown transcription factor networks regulate this dynamic change of features in memory CD8 T cells. The transcription factor ThPOK, also known as Zbtb7b, Zfp67, or cKrox, is essential for CD4 helper T cell development (8, 9). A spontaneous point mutation in the ThPOK gene is responsible for the helper T cell-deficient phenotype in the helper-deficient (HD) 4 mutant (called " ThPOK hd/hd mice " in this article) (8). In ThPOK hd/hd or ThPOK-deficient mice, MHC class II-restricted thymocytes are redirected to develop into the CD8 cytotoxic T cell lineage and to up-regulate CD8 cytotoxic T …