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Immunité et lymphocytes cytotoxiques

Disciplines Biology, Medicine - Health
Research fields

Cancerology, Immunology, Infectiology, Clinical research

Transcriptomics, Microbiology, Host-Parasite interactions/Symbiosis,
Experimental model: Human, Mammals

Dynamic systems
Supporting organisms HCL, Inserm, UCBL
Geographical location Domaine de Gerland - UCBL (Campus Charles Mérieux)
Lab CIRI
Team leader Jacqueline Marvel
Webpage http://ciri.inserm.fr/les-equipes/toutes-nos-equipes/immunite-et-lymphocytes-cytotoxiques/themes-de-recherches/


Memory CD8 T cells can be defined as antigen-experienced cells that display an improved response as compared to native 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 native 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.


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.