Blimp‐1 homolog Hobit identifies effector‐type lymphocytes in humans

Felipe A Vieira Braga, Kirsten M L Hertoghs, Natasja A M Kragten, Gina M Doody, Nicholas A Barnes, Ester B M Remmerswaal, Cheng-Chih Hsiao, Perry D Moerland, Diana Wouters, Ingrid A M Derks, Amber van Stijn, Marc Demkes, Jörg Hamann, Eric Eldering, Martijn A Nolte, Reuben M Tooze, Ineke J M ten Berge, Klaas P J M van Gisbergen, René A W van Lier

Human cytomegalovirus (CMV) induces the formation of effector CD8(+) T cells that are maintained for decades during the latent stage of infection. Effector CD8(+) T cells appear quiescent, but maintain constitutive cytolytic capacity and can immediately produce inflammatory cytokines such as IFN-γ after stimulation. It is unclear how effector CD8(+) T cells can be constitutively maintained in a terminal stage of effector differentiation in the absence of overt viral replication. We have recently described the zinc finger protein Homologue of Blimp-1 in T cells (Hobit) in murine NKT cells. Here, we show that human Hobit was uniformly expressed in effector-type CD8(+) T cells, but not in naive or in most memory CD8(+) T cells. Human CMV-specific but not influenza-specific CD8(+) T cells expressed high levels of Hobit. Consistent with the high homology between the DNA-binding Zinc Finger domains of Hobit and Blimp-1, Hobit displayed transcriptional activity at Blimp-1 target sites. Expression of Hobit strongly correlated with T-bet and IFN-γ expression within the CD8(+) T cell population. Furthermore, Hobit was both necessary and sufficient for the production of IFN-γ. These data implicate Hobit as a novel transcriptional regulator in quiescent human effector-type CD8(+) T cells that regulates their immediate effector functions. This article is protected by copyright. All rights reserved.