TSSP, a new therapeutic target to control or cure autoimmune diabetes: proof of concept – TSSP et T1D

The project rely on the generation of novel transgenic wice with targeted expression of TSSP in the relevant tissue. In parallel we will decipher the regulation of TSSP expression using in silico studies, genomic studies and molecular biology approach.

This study assess the potential of the strategy we propose in controlling the iset-reactive T cell repertoire to a level that permit sufficient control of the diabetogenic potential of islet reactive T cells. In addition, the charcaterization of TSSP regulation may permit the identification of compounds of clinical interest.

Within the 18 months covered by this grant we have generated the transgenic mice required for the project. We also identifyed a pathway that regulates TSSP expression that we are currently testing in vivo

Proof of concep, this project may allow the development of a novel strategy in the treatment of autoimmune diabetes

None at this stage

Type 1 diabetes is a complex autoimmune disease characterized by T cell-mediated destruction of pancreatic ß-cells. Both CD4 and CD8 T cells are critically involved and the absence of one functional subsets affect the course of disease. Diabetes development results from a loss of T cell tolerance to several islet antigens (Ag) and finding ways to re-establish tolerance to islet cells is the major challenge to control or cure diabetes. Given the increasing diversity of antigen repertoire driving autoimmunity most Ag therapy based on the delivery of one or two important islet Ag under tolerogenic conditions, have not yield significant disease improvement. Consequently combined Ag therapies are under consideration, though it remains possible that not all islet-Ag essential for diabetes progression have been identified.
We recently showed that the protease TSSP (Thymus specific serine protease) is a new protease of the class II presentation pathway that plays a critical role in diabetes development. Indeed we showed that TSSP-deficient (Tssp°) NOD mice, while immunocompetent, are completely protected from spontaneous diabetes and severe insulitis. Hence TSSP control a control a critical checkpoint in disease intiation/development. We found that diabetes resistance of Tssp° NOD mice results from intra-thymic deletion, by TSSP-deficient DC, of CD4 T cell specific for several islet Ag.
TSSP is expressed by thymic but not peripheral dendritic cells (DC). We showed that expression of TSSP by thymic DC impairs the presentation of some self-Ag and consequently prevent deletion of the corresponding autoreactive CD4 T cells. Though the mechanisms are still unknown, these results indicate that TSSP likely impairs the presentation by thymic DC of several islet-Ag that are critically involved in diabetes development. These observations suggest a new strategy of immunotherapy that may overcome the problems of Ag-specific therapy.
In this project we propose to test this novel strategy. We also propose to decipher the mechanisms that control TSSP expression in thymic DC. Hence this project will provide the proof of concept for an original strategy to control diabetes development and may provide the framework for translation into the clinic.