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Human Innate Immunity
U932 – Immunity and Cancer
Nicolas Manel
Team Leader, DR2 INSERM
[email protected]
Innate immune responses are considered the first
defensive line against harmful conditions, including
cancer.
Human dendritic cells play a key role in the
control of these responses and are a promising
constituent of rational immune therapies.
Indeed, dendritic cells possess a unique
machinery to detect and sense injured tissues,
cellular fragments and pathogens. Upon
detection, dendritic cells become licensed to
activate adaptive immunity and thus couple
innate and adaptive responses. We use HIV, an
important human pathogen that causes AIDS,
as a model to understand the regulation of
innate immunity in human dendritic cells
(Figure 1).
Figure 1: Capture of HIV-1 viral particles (green) by
two human dendritic cells.
We have discovered that an innate immune
response to HIV-1 exists in dendritic cells. HIV-1
is normally unable to infect dendritic cells and
we have used the Vpx protein found in other
lentiviruses to render dendritic cells susceptible
to HIV-1 infection. In these conditions, infection
of dendritic cells results in induction of an
innate immune response that can prime
adaptive immunity and induce protective
antiviral type I interferon. HIV-2, which is less
pathogenic than HIV-1, encodes Vpx and
naturally infects and induces an innate immune
response in dendritic cells, pointing to an
INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 1
Human Innate Immunity
U932 – Immunity and Cancer
important role of this response in determining
the ability of the immune system to control HIV
replication.
We recently showed that innate immune sensing of HIV by dendritic cells is mediated by the
cytosolic DNA sensor cGAS. In the virus, the viral DNA is required for cGAS activation. The viral
DNA is embedded in a shell of viral capsid proteins, and we showed that the viral capsid
determine the fate of the viral DNA towards viral replication or innate immune recognition. In
addition, we showed that the binding of host protein Cyclophilin A to capsid is a key regulator of
HIV sensing by dendritic cells.
Based on these findings, we now explore new
avenues of research. Our first aim is to identify
novel regulators of the innate immune
response and the viral replication. Our second
aim is to characterize the type of adaptive
immune response that will be generated in T
cells when the innate immune response to
HIV-1 is active in dendritic cells. Lastly, we
explore more general aspects of innate
immune regulation. In particular, we focus on
the regulation and functions of the important
sensor cGAS in immune cells. To achieve these
aims, we utilize a number of molecular and
cellular approaches, including RNAi in dendritic
cells, functional screens and analysis of gene
networks. Our results suggest new ways to
generate adjuvants for immunotherapies and
vaccines. A patent application has been filed
accordingly.
Figure 2: Human dendritic cells possess an intact
innate machinery to sense and respond to HIV.
This response requires cellular Cyclophilin A, leads
the production of type I interferon and licenses
dendritic cells for activation of naïve human T
lymphocytes. It is normally avoided by HIV-1, but
engaged by HIV-2, a less pathogenic virus.
INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 2
Human Innate Immunity
U932 – Immunity and Cancer
Key publications
Year of publication 2017
Cerboni S, Jeremiah N, Gentili M, Gehrmann U, Conrad C, Stolzenberg MC, Picard C, Neven B,
Fischer A, Amigorena S, Rieux-Laucat F, Manel N (2017 May 8)
Intrinsic antiproliferative activity of the innate sensor STING in T lymphocytes
The Journal of Experimental Medicine : DOI : 10.1084/jem.20161674
Year of publication 2016
Xavier Lahaye, Takeshi Satoh, Matteo Gentili, Silvia Cerboni, Aymeric Silvin, Cécile Conrad,
Abdelhakim Ahmed-Belkacem, Elisa C Rodriguez, Jean-François Guichou, Nathalie Bosquet,
Matthieu Piel, Roger Le Grand, Megan C King, Jean-Michel Pawlotsky, Nicolas Manel (2016 May 7)
Nuclear Envelope Protein SUN2 Promotes Cyclophilin-A-Dependent Steps of HIV
Replication.
Cell reports : DOI : S2211-1247(16)30363-1
M Raab, M Gentili, H de Belly, H R Thiam, P Vargas, A J Jimenez, F Lautenschlaeger, Raphaël
Voituriez, A M Lennon-Duménil, N Manel, M Piel (2016 Apr 15)
ESCRT III repairs nuclear envelope ruptures during cell migration to limit DNA
damage and cell death
Science (New York, N.Y.) : DOI : 10.1126/science.aad7611
Year of publication 2015
INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 3
Human Innate Immunity
U932 – Immunity and Cancer
Gentili M, Kowal 1, Tkach M, Satoh T, Lahaye X, Conrad C, Boyron M, Lombard B, Durand S,
Kroemer G, Loew D, Dalod M, Théry C, Manel N. (2015 Jul 30)
Transmission of innate immune signaling by packaging of cGAMP in viral
particles.
Science : DOI : 10.1126/science.aab3628
Year of publication 2013
Xavier Lahaye, Takeshi Satoh, Matteo Gentili, Silvia Cerboni, Cécile Conrad, Ilse Hurbain, Ahmed
El Marjou, Christine Lacabaratz, Jean-Daniel Lelièvre, Nicolas Manel (2013 Sep 6)
The capsids of HIV-1 and HIV-2 determine immune detection of the viral cDNA
by the innate sensor cGAS in dendritic cells.
Immunity : 1132-42 : DOI : 10.1016/j.immuni.2013.11.002
Year of publication 2011
Nicolas Manel, Dan R Littman (2011 Jul 14)
Hiding in plain sight: how HIV evades innate immune responses.
Cell : 271-4 : DOI : 10.1016/j.cell.2011.09.010
INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 4