Blanc SVSE 3 - Blanc - SVSE 3 - Microbiologie, immunologie, infectiologie

Cellular stress sensing by human gamma/delta T cells – GDSTRESS

Immune sensing of cellular stress by human gamma/delta T cells

T cells express antigen recognition receptors made of two glycoprotein subunits encoded by either alpha/beta or gamma/delta genes, the diversity of which is generated by somatic gene recombination. The nature of antigens recognized by gd T cells and their precise activation modalities in response to tissue insults remain debated.

Antigen specificity of human gd T cells : physiopathological and therapeutic implications

The project aims at testing, through analysis of the antigen specificity and activation modalities of human gd T cells, whether these cells recognize related ligands (like their ab T cell counterparts) or can sense stress-induced changes of conformation, topology or molecular environment of intrinsically diverse ligands.

Through varied cellular, biochemical, molecular and structural approaches, we will test whether several new receptors recently involved in gd T cell activation, such as EPCR, EphA2, HFC and BTN3A1, are cognate TCR ligands or if sensing of these molecules results from stress induced topological changes. To assess the physiopathological relevance of these TCR/ligand systems, we will determine in adhoc in vitro and in vivo settings whether gd T cell activation or anergy can be linked to alterations of BTN3, EPCR or EphA2 expression.

During the first 6 months, our ongoing studies have confirmed the recognition of EphA2 and HLA I free chains by gd TCR derived from in vivo expanded T cells clones in patients undergoing HCMV infection. They have also confirmed the key role played by BTN3A1 in the activation of some human gd T cell subsets by phosphoisoprenoid metabolites. New immunotherapeutic strategies targeting human gd T cells have been also tested in in vivo preclinical models.

This project should improve our understanding of the immunobiology of gd T cells, which represent promising immunotherapeutic targets owing to their marked implication in varied infectious and oncological diseases

Santolaria T et al. J Immunol sous presse

T lymphocytes expressing gd T cell receptors (gd T cells) contribute to immunity against infections and tumors through sensing of conserved cellular stress-induced signals and antigens, whose nature remains in most instances elusive. The gd TCR ligands identified so far have turned out to be highly heterogeneous, consistent with an "Ig-like" mode of antigenic recognition by this kind of TCR. Therefore it is currently unclear whether gd TCR have co-evolved with counter-receptors with related molecular patterns (as is the case for aß T cells and MHC molecules), or whether these receptors sense stress-induced changes of the conformation, topology or molecular environment of inherently diverse ligands. Addressing these issues should improve our understanding of the biology of gd T cells, which represent promising immunotherapeutic targets owing to their wide implication in infectious and oncogenic diseases.

The present proposal aims at testing this hypothesis in several human gd T cell systems, for which the participating teams recently characterized new target molecules that are mandatory for their TCR-dependent activation. These teams recently identified surface receptors (butyrophilin-like 3 (BTN3/CD277), Endothelial Protein C Receptor (EPCR), Ephrin A2 (EphA2) and HLA-B) that play a unique and key role in the recognition of transformed and infected target cells and the ensuing activation of several human gd T cell subsets. Using a broad array of cellular, biochemical, molecular and structural approaches, we will test whether the above molecules are bona fide gd TCR ligands, and/or whether gd TCR signaling primarily results from topological changes of these molecules or their partners. In order to assess the physiopathological relevance of gd T cell recognition of these newly identified molecules, we will determine in ad hoc in vitro and in vivo models whether altered expression of BTN3, EPCR and EphA2 in infectious or tumor contexts could underly gd T cell expansion or anergization occuring in these situations.

This project will involve three teams with complementary expertise on the immunobiology of human gd T cells and T cell costimulation. It will benefit longstanding and fruitful collaborations already established between the participating teams and with prominent structural biologists (B. Willcox, Birmingham, UK and E.J. Adams, Chicago, IL). Its good feasibility and competitiveness is supported by (i) a large set of original results recently obtained by the participating teams, that describe several new key actors involved in human gd T cell activation, (ii) readily available tools and models directly relevant to the project and (iii) broad technical skills of the partners which should allow transdisciplinary assessment of the above issues.

In summary, this project should provide new insights into the nature and distribution of the antigens recognized by human gd T cells. Besides fundamental implications regarding the mechanisms underlying gd T cell receptor coevolution with their ligands, this knowledge may prove useful for the implementation and optimization of immunotherapies targeting gd T cells.

Project coordinator

Monsieur Marc BONNEVILLE (Centre de Recherche en Cancérologie Nantes Angers) – bonnevil@nantes.inserm.fr

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

UMR5164 CNRS Université de Bordeaux 2 / CNRS
INSERM - CRCM Centre de Recherche en Cance´rologie de Marseille
UMR_S892 INSERM Centre de Recherche en Cancérologie Nantes Angers

Help of the ANR 400,000 euros
Beginning and duration of the scientific project: December 2012 - 36 Months

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