Intrinsic roles of heat shock proteins in T-cell biology

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Heat shock proteins (HSPs) are the most conserved proteins present in all organisms. HSP expression is induced not only in hostile environments, but also under normal growth conditions where human cells have to handle the stress associated with activation, differentiation and the production of reactive oxygen species. Intracellular HSPs actively perform a number of "house-keeping" tasks through direct bindings including post-translational protein assembly and translocation, and cytoprotection. Several HSPs have been reported to play important roles in innate immunity illustrated by enhanced cell maturation and antigen presentation to specific T-lymphocytes. Our recent data clearly show higher intracellular expression of HSP70 and HSP60 in memory CD4 T-cells when compared to the naive population.****Although our basic knowledge regarding molecular events dictating T-cell immunity is increasing, the role of HSPs on the generation and maintenance of long-lasting memory cells has not been investigated before. Memory CD4 T-cell compartment plays a central role in our defense system by orchestrating the help to other populations, and producing an array of cytokines and soluble factors. Memory CD4 T-cells are known to be long-lasting populations, able to protect themselves against apoptosis and various insults. A few years ago, we demonstrated the critical involvement of the transcriptional factor FOXO3a in the survival of long-term memory CD4 T-populations. In my research program, our laboratory aims to unveil the contribution of the HSP family in adaptive immunity, and increase our incomplete knowledge of T-cell biology. In this proposal, we hypothesize that HSPs play a critical role in protecting long-term memory CD4 T-cells from apoptosis and in maintaining this population. We will focus on two intracellular HSPs, the HSP70 and HSP60. More specifically, by using an in vitro linear differentiation model and ex vivo highly purified cells, the objectives will be to understand the molecular mechanisms responsible for increased HSP expression, and their roles on T-cell integrity during the generation and maintenance of memory CD4 T-cells.****To conclude, the anticipated outcomes and the benefits to the research field and to Canada will be ensured in our research program by providing the evidence of a new molecular mechanism that plays a critical role on memory CD4 T-cell biology. In the long term run, my lab is also interested to assess HSP implication during the generation of T-cell immunological synapse following antigen stimulation, lineage commitment and plasticity, cell-cycling and cytokine production, as well as maturation and clonal selection process in thymus.******