title: The Transcription Factor Hobit Identifies Human Cytotoxic CD4+T Cells.
abstract: The T cell lineage is commonly divided into CD4-expressing helper T cells that polarize immune responses through cytokine secretion and CD8-expressing cytotoxic T cells that eliminate infected target cells by virtue of the release of cytotoxic molecules. Recently, a population of CD4+T cells that conforms to the phenotype of cytotoxic CD8+T cells has received increased recognition. These cytotoxic CD4+T cells display constitutive expression of granzyme B and perforin at the protein level and mediate HLA class II-dependent killing of target cells. In humans, this cytotoxic profile is found within the human cytomegalovirus (hCMV)-specific, but not within the influenza- or Epstein-Barr virus-specific CD4+T cell populations, suggesting that, in particular, hCMV infection induces the formation of cytotoxic CD4+T cells. We have previously described that the transcription factor Homolog of Blimp-1 in T cells (Hobit) is specifically upregulated in CD45RA+effector CD8+T cells that arise after hCMV infection. Here, we describe the expression pattern of Hobit in human CD4+T cells. We found Hobit expression in cytotoxic CD4+T cells and accumulation of Hobit+CD4+T cells after primary hCMV infection. The Hobit+CD4+T cells displayed highly overlapping characteristics with Hobit+CD8+T cells, including the expression of cytotoxic molecules, T-bet, and CX3CR1. Interestingly, γδ+T cells that arise after hCMV infection also upregulate Hobit expression and display a similar effector phenotype as cytotoxic CD4+and CD8+T cells. These findings suggest a shared differentiation pathway in CD4+, CD8+, and γδ+T cells that may involve Hobit-driven acquisition of long-lived cytotoxic effector function.
authors.affiliation: Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory , Amsterdam , Netherlands.
authors.forename: Anna E
authors.initials: AE
authors.lastname: Oja
authors.affiliation: Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory , Amsterdam , Netherlands.
authors.forename: Felipe A
authors.initials: FA
authors.lastname: Vieira Braga
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, Amsterdam, Netherlands; Renal Transplant Unit, Division of Internal Medicine, Academic Medical Centre, Amsterdam-Zuidoost, Netherlands.
authors.forename: Ester B M
authors.initials: EB
authors.lastname: Remmerswaal
authors.affiliation: Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory , Amsterdam , Netherlands.
authors.forename: Natasja A M
authors.initials: NA
authors.lastname: Kragten
authors.affiliation: Department of Experimental Immunology, Academic Medical Center , Amsterdam , Netherlands.
authors.forename: Kirsten M L
authors.initials: KM
authors.lastname: Hertoghs
authors.affiliation: College of Medical and Dental Sciences, Institute of Immunology and Immunotherapy, University of Birmingham , Edgbaston, Birmingham , UK.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Zuo
authors.affiliation: College of Medical and Dental Sciences, Institute of Immunology and Immunotherapy, University of Birmingham , Edgbaston, Birmingham , UK.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Moss
authors.affiliation: Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory , Amsterdam , Netherlands.
authors.forename: René A W
authors.initials: RA
authors.lastname: van Lier
authors.affiliation: Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Amsterdam, Netherlands; Department of Experimental Immunology, Academic Medical Center, Amsterdam, Netherlands.
authors.forename: Klaas P J M
authors.initials: KP
authors.lastname: van Gisbergen
authors.affiliation: Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory , Amsterdam , Netherlands.
authors.forename: Pleun
authors.initials: P
authors.lastname: Hombrink
keywords: CD4+ T cells; Hobit; cytotoxic; human; human cytomegalovirus