T cell hyporesponsiveness to TSC2null cells suggests bidirectional interactions in LAM

Lymphangioleiomyomatosis (LAM) is a rare disease characterized by the proliferation of neoplastic smooth muscle-like cells in women. The role of the immune system in LAM progression is unclear.

Investigate the influence of T cells on TSC2null smooth muscle cell behaviour at cellular and transcriptome levels.

Archival LAM and control lung tissues were compared by gene profiling with NanoString analyses where elevated CD8 T cell accumulation was observed in LAM vs. control tissues. Acknowledging the limited translational potential of animal models, a human T cell-TSC2null smooth muscle cell co-culture system was established and cell phenotype and proliferation over time using flow cytometry was examined.

TSC2null smooth muscle cells adopt cancer-associated fibroblast (CAF)-like phenotypes, which could be regulated by IFN-γ. TSC2null cells suppressed T cell proliferation and induced T cell anergic phenotypes, which could not be reversed by antigen receptor and co-stimulation. TSC2null cells decreased expression of co-stimulatory molecule, CD40, and increased proliferation in the presence of T cells, yet underwent apoptosis in the presence of activated T cells.

Our findings suggest a contact-dependent feedback loop between TSC2null smooth muscle cells and T cells, which may both promote immune dysregulation in LAM and explain the invasive behavior and tissue remodeling observed clinically.