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IFR 128 BioSciences Gerland - Lyon Sud |
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U851 INSERM – UCBL – HCL |
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Team: APOPTOSIS and
CD8 T cells MEMORY |
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Team leader: Jacqueline Marvel |
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Current project |
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CD8 T CELLS MEMORY – T INFLAMMATORY
MEMORY CELLS (TIM) Memory CD8 T cells can be defined as antigen-experienced cells that
display an improved response as compared to naïve cells. This has been shown
to result from an increase in antigen-specific cell numbers following the initial
encounter, but also from the accelerated acquisition of effector functions by
memory cells. Our group studies the phenotypic and functional characteristics
associated with memory CD8 T cell differentiation, as well as the factors
controlling their generation. The memory CD8 T cell population is
heterogeneous, comprising at least two well-described subsets: T Effector and
T Central Memory Cells (TEM and TCM, respectively). Most memory CD8 T cell
subsets that have been hitherto defined are generated in response to
infectious pathogens or in the presence of molecular signals (PAMPs) that
mimic pathogens. However, CD8 T cells can also mount responses (directed
against emerging tumour cells, transplant antigen or allergens …) in
sterile, non-infectious, contexts. We have recently characterized, in mice,
the memory CD8 T cell subset generated under such sterile inflammatory
conditions (Mbitikon-Kobo et al., 2009). These T Inflammatory Memory cells
(TIM) are characterized by the acquisition of several functional, phenotypic
and molecular traits that distinguish them from naïve and virus-induced
classical memory CD8 T cells and we could show that they are involved in
hyper-sensitivity reactions that model contact allergy in humans. We are
currently studying this new memory CD8 T cell subset, along several lines of
investigation: • the role of TIM in
responses to pathogens and tumours; • quest for specific molecular
markers of TIM cells; • identification of TIM
cells in humans; • the role of TIM and
other memory CD8 T cell subsets in a Th2-pathology, asthma. REGULATION AND ROLE OF CCL5 IN THE MEMORY IMMUNE RESPONSE The efficiency of CD8 memory response relies
in part on the improvement of effectors functions such as cytokine secretion .We have
identified a number of genes that are more expressed in memory CD8 T
cells compared to naive CD8 T cells. One of them codes for the RANTES
chemokine (CCL5). We have shown that high levels of untranslated mRNA coding
for that cytokine are found in memory CD8 T cells. We are currently working
on the mechanisms that are responsible for the maintenance of these high
levels of CCL5 mRNA in memory CD8 T cells. We have recently demonstrated that memory CD8 T cells produce CCL5
protein immediately upon TCR triggering. This rapid production correlates
with the maintenance of high levels of untranslated CCL5 mRNA. The role of this CCL5 production in memory T cells functions, are unknown. To test the function of the immediate CCL5
production in the functions of memory T cells, we have developed a
peptide-specific model of contact hypersensitivity. We have shown that the
maintenance of untranslated CCL5 mRNA stores relies on the cell autonomous
chronic transcription of CCL5. The level of CCL5 are however still regulated
as IL4 can inhibit CCL5 transcription reading to CCL5 mRNA stores depletion
and abrogation of the immediate CCL5 production capacity of CD8 T cells. We are currently developing a number of
experimental systems to test the potential role of CCL5 in the CD8 memory response. DENDRITIC CELLS AND CROSS
PRESENTATION Dendritic cells (DC) are bone marrow-derived antigen-presenting cells that play a crucial role in inducing adaptive immune responses to foreign antigens and in maintaining T cell tolerance (i.e. the silencing of clones reacting to self antigens). DC and their precursors originate from bone-marrow and traffic to lymphoid and non lymphoid organs. Differentiated DC are present in multiple tissues as efficient endocytic cells but immunologically immature. Upon encounter of danger signals such as pathogen-derived compounds or endogenous alarmins recognised through Toll-like receptors (TLR), lectins or Nod-like receptors, DC undergo developmental changes allowing their migration to lymph nodes and the expression of molecules involved in antigen presentation to T cells. In vivo, cells undergoing apoptosis during
development, tissue homeostasis, in response to injury or microbes are
quickly removed. The phagocytosis of
dying cells by DC lead to the processing of dead cell-associated antigens and
to the cross presentation of the resulting peptides onto MHC class I
molecules. This seems to be crucial for the induction of either cross-priming
or tolerance of the CD8 T lymphocytes. Among the distinct subsets of DC that have
been described, CD8a+ DC have a crucial role in the uptake and the cross
presentation of dead cell associated antigens. Our aim is to compare the ability of different DC subsets
to cross present dead cell-associated antigens to CD8 T cells and to
establish whether this activation leads to memory generation. Bone marrow-derived
cultures have been commonly used to generate various DC subsets such
as the equivalent of in vivo inflammatory TipDC, pDC, CD8α+
and CD8α- DC precursors. Our results show
that TLR ligand can licence some DC subsets to induce the proliferation
of dead cell antigen specific CD8 T cells allowing memory generation.
Our current projects are to define the mechanism(s) of dead-cell associated
cross-presentation licensing by TLR ligand and to study the impact of
the antigen carrying cell and the apoptotic pathway on the immunogenic
potential.
Nibbling of necrotic
cell (green) by FLT3-L-derived dendritic cell (red) C. De Brito, J.
Marvel and Y. Leverrier (Inserm U851 and Imaging facility, IFR128
Biosciences, Lyon) ACTIVATION OF AN INTRINSIC INNATE IMMUNE RESPONSE FOLLOWING AN
ONCOGENIC STRESS The role of the immune system in the control of tumour has been the
purpose of multiple studies. Although in some circumstances the immune system
can promote tumour development, an increasing body of evidences supports a
role for the immune system in detecting and eliminating pre-clinical cancer
cells (a phenomenon called immuno-surveillance). Finally, recent data also
suggest that tumour cells can provide signals that activate the immune system. In this context of interplay between tumour and immunity, an original
observation in the lab was that perturbation of transcription, that can be
assimilated to an oncogenic stress, induces the early expression of more than
100 genes associated with the intrinsic innate response. This response is
characterised by the induction of interferon-induced genes as well as genes
implicated in exogenous or endogenous dangers sensing pathways. As the
activation of the cellular intrinsic innate immune system upon early
oncogenic activation may be involved in triggering the immuno-surveillance
process to function, understanding how oncogene stress can lead to innate
sensors activation may offer the possibility of developing novel cancer
therapeutic strategies. Group
members : |
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Jacqueline
Marvel |
Ph.D
– Team leader |
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| Yann
Leverrier |
Ph.D |
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| Christophe
Arpin |
Ph.D |
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| Gilles
Devouassoux |
MD-PhD |
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| Marie-Cécile
Michallet |
Post
doctorant |
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| Stephane Schicklin | Bioinformatics engineer | ||
| Erwann
Ventre |
Ph.D
student |
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| Virginie
Jubin |
MD-Ph.D
student |
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| Joel
Baguet |
Research
Assistant (IR) |
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| Martine
Tomkowiak |
Research
Assistant (IE2) |
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| Sophia
Djebali |
Research
Assistant (IE1) |
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| Julien Mafille | Research Assistant (AI) | ||
| Solène Chambion | Research Assistant (TR) | ||
| Publications |
| Deniaud
E, Baguet J, Chalard R, Blanquier B, Brinza L, Meunier J, Michallet MC,
Laugraud A, Ah-Soon C, Wierinckx A, Castellazzi M, Lachuer J, Gautier
C, Marvel J, Leverrier Y. Overexpression of transcription factor Sp1 leads to gene expression perturbations and cell cycle inhibition. PLoS One. 2009 Sep 15;4(9):e7035. |
| Mbitikon-Kobo FM,
Vocanson M, Michallet MC, Tomkowiak M, Cottalorda A, Angelov GS, Coupet
CA, Djebali S, Marçais A, Dubois B, Bonnefoy-Bérard N, Nicolas JF, Arpin
C, Marvel J. Characterization
of a CD44/CD122int memory CD8 T cell subset generated under sterile
inflammatory conditions |
| Mercier BC, Cottalorda A, Coupet CA, Marvel J, Bonnefoy-Bérard
N. TLR2 engagement
on CD8 T cells enables generation of functional memory cells in response
to a suboptimal TCR signal. |
| Grégoire C, Cognet C, Chasson L, Coupet CA, Dalod
M, Reboldi A, Marvel J, Sallusto F, Vivier E, Walzer T. Intrasplenic trafficking
of natural killer cells is redirected by chemokines upon inflammation. |
| Dong W., Arpin
C., Accardi R., Gissmann L., Sylla B.S., Marvel J. and Tommasino M.
Loss of p53 or
p73 in human papillomavirus type 38 E6 and E7 transgenic mice partially
restores the UV-activated cell cycle checkpoints |
| Marçais A., Tomkowiak M., Walzer T., Coupet C.-A.,
Ravel-Chapuis A. and Marvel J. Maintenance of
CCL5 mRNA stores by memory CD8 T cells is dependent on transcription
and is coupled to increased mRNA stability. |
| Deniaud E, Baguet
J., Mathieu A-L, Page G, Marvel J and Leverrier Y. Overexpression
of Sp1 transcription factor induces apoptosis |