Opposing Development of Cytotoxic and Follicular Helper CD4 T Cells Controlled by the TCF-1-Bcl6 Nexus.
CD4+T cells develop distinct and often contrasting helper, regulatory, or cytotoxic activities. Typically a property of CD8+T cells, granzyme-mediated cytotoxic T cell (CTL) potential is also exerted by CD4+T cells. However, the conditions that induce CD4+CTLs are not entirely understood. Using single-cell transcriptional profiling, we uncover a unique signature of Granzyme B (GzmB)+CD4+CTLs, which distinguishes them from other CD4+T helper (Th) cells, including Th1 cells, and strongly contrasts with the follicular helper T (Tfh) cell signature. The balance between CD4+CTL and Tfh differentiation heavily depends on the class of infecting virus and is jointly regulated by the Tfh-related transcription factors Bcl6 and Tcf7 (encoding TCF-1) and by the expression of the inhibitory receptors PD-1 and LAG3. This unique profile of CD4+CTLs offers targets for their study, and its antagonism by the Tfh program separates CD4+T cells with either helper or killer functions.
Retroviral Immunology, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
Tiziano
T
Donnarumma
Retroviral Immunology, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Retrovirus-Host Interactions, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
George R
GR
Young
Retroviral Immunology, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
Julia
J
Merkenschlager
Retroviral Immunology, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
Urszula
U
Eksmond
Institute for Virology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany.
Nadine
N
Bongard
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
Stephen L
SL
Nutt
Centre d'Immunologie de Marseille-Luminy (CIML), Aix-Marseille University, UM2, Marseille 13288, France.
Claude
C
Boyer
Institute for Virology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany.
Ulf
U
Dittmer
Institute for Virology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany.
Vu Thuy Khanh
VT
Le-Trilling
Institute for Virology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany.
Mirko
M
Trilling
Institute for Virology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany.
Wibke
W
Bayer
Retroviral Immunology, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Department of Medicine, Faculty of Medicine, Imperial College London, London W2 1PG, UK. Electronic address: george.kassiotis@crick.ac.uk.
George
G
Kassiotis
D000818:Animals; D059447:Cell Cycle Checkpoints; D053804:Granzymes / Q000378:metabolism; D051379:Mice; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000378:metabolism*; D012190:Retroviridae / Q000502:physiology; D051822:T Cell Transcription Factor 1 / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology* / Q000378:metabolism*; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000378:metabolism*; D014158:Transcription, Genetic
D051560:Proto-Oncogene Proteins c-bcl-6; D051822:T Cell Transcription Factor 1; D053804:Granzymes; C509214:Gzmb protein, mouse
CD4 T cell differentiation; adenovirus-based vaccination; antiviral immunity; cytotoxic CD4 T cells; inhibitory receptors; retroviral infection; single-cell RNA sequencing