title: CXCR5(+) follicular cytotoxic T cells control viral infection in B cell follicles.
abstract: During unresolved infections, some viruses escape immunological control and establish a persistant reservoir in certain cell types, such as human immunodeficiency virus (HIV), which persists in follicular helper T cells (TFH cells), and Epstein-Barr virus (EBV), which persists in B cells. Here we identified a specialized group of cytotoxic T cells (TC cells) that expressed the chemokine receptor CXCR5, selectively entered B cell follicles and eradicated infected TFH cells and B cells. The differentiation of these cells, which we have called 'follicular cytotoxic T cells' (TFC cells), required the transcription factors Bcl6, E2A and TCF-1 but was inhibited by the transcriptional regulators Blimp1, Id2 and Id3. Blimp1 and E2A directly regulated Cxcr5 expression and, together with Bcl6 and TCF-1, formed a transcriptional circuit that guided TFC cell development. The identification of TFC cells has far-reaching implications for the development of strategies to control infections that target B cells and TFH cells and to treat B cell-derived malignancies.
authors.affiliation: Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia.
authors.forename: Yew Ann
authors.initials: YA
authors.lastname: Leong
authors.affiliation: Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia.
authors.forename: Hong Sheng
authors.initials: HS
authors.lastname: Ong
authors.affiliation: School of Dentistry, The University of North Carolina at Chapel Hill, North Carolina, USA.
authors.forename: Di
authors.initials: D
authors.lastname: Wu
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.|The Department of Medical Biology, University of Melbourne, Parkville, Australia.
authors.forename: Kevin
authors.initials: K
authors.lastname: Man
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Claire
authors.initials: C
authors.lastname: Deleage
authors.affiliation: Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria.
authors.forename: Martina
authors.initials: M
authors.lastname: Minnich
authors.affiliation: Institute of Immunology and Immunotherapy, Centre for Human Virology and Cancer Immunology and Immunotherapy Centre, University of Birmingham, UK.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Meckiff
authors.affiliation: Shandong Analysis and Test Center, Shandong Academy of Sciences, Jinan, China.
authors.forename: Yunbo
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Shandong Analysis and Test Center, Shandong Academy of Sciences, Jinan, China.
authors.forename: Zhaohua
authors.initials: Z
authors.lastname: Hou
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.|The Department of Medical Biology, University of Melbourne, Parkville, Australia.
authors.forename: Dimitra
authors.initials: D
authors.lastname: Zotos
authors.affiliation: Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, Australia.
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Fenix
authors.affiliation: Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia.
authors.forename: Anurag
authors.initials: A
authors.lastname: Atnerkar
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.|The Department of Medical Biology, University of Melbourne, Parkville, Australia.
authors.forename: Simon
authors.initials: S
authors.lastname: Preston
authors.affiliation: Department of Surgery, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Chipman
authors.affiliation: Department of Surgery, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Greg J
authors.initials: GJ
authors.lastname: Beilman
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.|The Department of Medical Biology, University of Melbourne, Parkville, Australia.
authors.forename: Cody C
authors.initials: CC
authors.lastname: Allison
authors.affiliation: Department of Pathology, Beijing Ditan Hospital, Capital Medical University, Beijing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Pathology, Beijing Ditan Hospital, Capital Medical University, Beijing, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Jiawei
authors.initials: J
authors.lastname: Xu
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.|The Department of Medical Biology, University of Melbourne, Parkville, Australia.
authors.forename: Jesse G
authors.initials: JG
authors.lastname: Toe
authors.affiliation: The Peter Doherty Institute for Infection and Immunity, University of Melbourne and Royal Melbourne Hospital, Melbourne, Australia.
authors.forename: Hao K
authors.initials: HK
authors.lastname: Lu
authors.affiliation: Department of Ophthalmology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Tao
authors.affiliation: Centenary Institute, Newtown, Australia.
authors.forename: Umaimainthan
authors.initials: U
authors.lastname: Palendira
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Dent
authors.affiliation: Department of Immunology/Microbiology, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: Alan L
authors.initials: AL
authors.lastname: Landay
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.|The Department of Medical Biology, University of Melbourne, Parkville, Australia.
authors.forename: Marc
authors.initials: M
authors.lastname: Pellegrini
authors.affiliation: Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, Australia.
authors.forename: Iain
authors.initials: I
authors.lastname: Comerford
authors.affiliation: Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, Australia.
authors.forename: Shaun R
authors.initials: SR
authors.lastname: McColl
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Schacker
authors.affiliation: Institute of Immunology and Immunotherapy, Centre for Human Virology and Cancer Immunology and Immunotherapy Centre, University of Birmingham, UK.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Long
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Jacob D
authors.initials: JD
authors.lastname: Estes
authors.affiliation: Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria.
authors.forename: Meinrad
authors.initials: M
authors.lastname: Busslinger
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.|The Department of Medical Biology, University of Melbourne, Parkville, Australia.
authors.forename: Gabrielle T
authors.initials: GT
authors.lastname: Belz
authors.affiliation: The Peter Doherty Institute for Infection and Immunity, University of Melbourne and Royal Melbourne Hospital, Melbourne, Australia.|Department of Infectious Diseases, The Alfred Hospital, Monash University, Melbourne, Australia.
authors.forename: Sharon R
authors.initials: SR
authors.lastname: Lewin
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.|The Department of Medical Biology, University of Melbourne, Parkville, Australia.
authors.forename: Axel
authors.initials: A
authors.lastname: Kallies
authors.affiliation: Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia.|Shandong Analysis and Test Center, Shandong Academy of Sciences, Jinan, China.|Centre for Inflammatory Diseases, School of Clinical Sciences, Monash University, Clayton, Australia.
authors.forename: Di
authors.identifier: 0000-0003-1721-8922
authors.initials: D
authors.lastname: Yu
mesh_terms: D000818:Animals; D001117:Arenaviridae Infections / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D020031:Epstein-Barr Virus Infections / Q000276:immunology*; D005786:Gene Expression Regulation; D018858:Germinal Center / Q000473:pathology / Q000821:virology; D006678:HIV / Q000276:immunology*; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000074462:Positive Regulatory Domain I-Binding Factor 1; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000235:genetics / Q000378:metabolism; D054380:Receptors, CXCR5 / Q000235:genetics / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051538:Hepatocyte Nuclear Factor 1-alpha; D000074462:Positive Regulatory Domain I-Binding Factor 1; D051560:Proto-Oncogene Proteins c-bcl-6; D054380:Receptors, CXCR5; D014157:Transcription Factors; C490010:Bcl6 protein, mouse; C095085:CXCR5 protein, human; C496488:Hnf1a protein, mouse; C513258:Prdm1 protein, mouse; C075668:Tcf3 protein, mouse