T cells chronically stimulated by persistent antigen often become functionally exhausted and do not respond appropriately to therapeutic vaccination. Therefore, understanding the biology of T cells chronically stimulated by persistent antigens is a prerequisite to the development of therapeutic vaccine strategies aimed at boosting more effectively endogenous T cell responses against chronic viral infections and cancers.
The specific aim of WP3 is to gain knowledge on the immune mechanisms that allow the concomitant persistence of specific T cells and their antigen. We will first take advantage of a murine model of T cell exhaustion that has been previously developed within this consortium and identify a molecular signature (transcriptome analysis) in the signalling cascade of dysfunctional cells. A similar functional defect has been identified in human T cells isolated from CMV infected infants, a subset of T cells characterized by the loss of expression of the CD28 marker, and work will be performed to confirm a signalling defect in these cells.
Notably, cells lacking CD28 have been recently identified within our consortium in multiple sclerosis patients, a clinical situation whereby self antigen specific T cells are under chronic stimulation. Finally, a signalling defect in tumour specific T cells has been also recently described in one of the participating teams, revealing again a clinical situation in which continuous presence of an antigen causes unresponsiveness in specific T cells. The long term objective of this WP is to devise strategies to revive function in exhausted cells during infection or in cancer patients, while reinforcing this unresponsive state in autoimmune diseases.