Understanding the pathophysiological mechanisms associated with mutations in TIM-3 – TIM3-PHYSIOPAT

Recently, we identified missense mutations in HAVCR2 (coding gene for TIM-3) as a genetic cause of a newly described genetic disorder characterized by hemophagocytic lymphohistiocytosis (HLH) associated to sub-cutaneous panniculitis-like T-cell lymphoma (SPTCL).
HLH is a rare life-threatening condition that manifests as an uncontrolled activation of lymphocytes and macrophages, accompanied by massive inflammatory hypercytokinemia. SPTCL is an uncommon non-Hodgkin cutaneous T-cell lymphoma affecting the sub-cutaneous adipose tissue.
Tim-3 acts as a negative immune checkpoint by inhibiting the immune response. TIM-3 mutations identified in patients impair protein folding and induce the intracellular retention, preventing plasma membrane expression on patients’ cells. In keeping with the immune regulatory role of TIM-3, patients present with persistent immune activation and increased production of inflammatory cytokines.
The TIM3-PHYSIOPAT project seeks to characterize the mechanisms maintaining immune homeostasis and preventing HLH and SPTCL development. We aim (i) to identify new genetic causes of underlying this condition, (ii) to identify immune regulatory pathway(s) preventing HLH and SPTCL development, and (ii) to unveil the pathophysiological mechanism(s) responsible of this severe immune disorder. To do so, we shall leverage patients’ samples and an newly developed murine model which recapitulate human pathology to perform a single-cell transcriptomic approach and in vivo functional assays. This approach will allow us to reveal transcriptional signatures associated to HLH and SPTCL development, and gain valuable insights into the cellular and molecular mechanisms by which TIM-3 prevents the development of this severe condition. Altogether, the TIM3-PHYSIOPAT project aim to improve diagnosis by identifying mutation in new causative genes, and set the path to the development of more efficient therapeutic strategies for patients.