Regulation of T cell cytotoxicity during chronic antigen stimulation

About This Grant

PROJECT SUMMARY/ABSTRACT CD8 T cells are important immune mediators central to protection against intracellular pathogens and cancer. Regulation of the delicate balance between T cell activation and quiescence is essential for mounting effective immune responses while preventing excessive inflammation. T cell dysfunction resulting from chronic antigen stimulation, known as “exhaustion”, leads to loss of protection against infections and cancer. In part related to this, chimeric antigen receptor (CAR)-T cell therapy has faced major challenges in eradicating solid tumors, with data demonstrating that the high antigen load contributes to chronic stimulation through the CAR, driving an exhausted phenotype. Conversely, an overactive and dysregulated T cell response can cause inflammatory disorders, including autoimmunity and graft-versus-host disease (GVHD), a deadly immune complications of hematopoietic stem cell transplant (HCT). Thus, effectively controlling T cell activation is key both to harnessing their potential to control infection and malignancies, and to managing pathologically inflammatory conditions. The transcription factor Hobit (ZNF683) has emerged as a novel central regulator for T cell activation and cytotoxicity. First identified as a lineage-specific marker of resident-memory T cells, Hobit has also been discovered across several cancer clinical trials to be expressed by exhausted anti-tumor T cells re-animated by PD-1 blockade. Hobit expression is lost in terminally exhausted T cells, suggesting a malleable role in T cell quiescence and re-activation. Compelling new work from our lab has deepened this paradigm shift: In the pivotal clinical trial that led to FDA approval of the CD28:CD80/86 co-stimulation blockade agent, abatacept, for GVHD prevention, we found that Hobit was significantly downregulated in the inflammatory proliferating T cells that normally precede acute GVHD (aGVHD), and that this downregulation was controlled with abatacept. Our goal is to uncover how Hobit governs T cell activation under chronic antigen stimulation and develop strategies to harness this pathway. We hypothesize that Hobit maintains antigen-experienced CD8 T cells in a state of revivable quiescence, which prevents terminal exhaustion and preserves their cytotoxic potential. To improve the outcomes of cellular therapies—by suppressing alloreactive T cells after HCT or enhancing persistence of CAR-T cells against tumor and antiviral T cells for chronic infections—it is critical to elucidate the molecular switches that control T cell cytotoxicity in the face of chronic antigen. We will approach this question through the following Aims: Aim 1: Determine if Hobit can preserve cytotoxicity in exhausted CD8 T cells. We hypothesize that Hobit can preserve cytotoxic potential in chronically stimulated CD8 T cells by inhibiting Blimp-1-mediated terminal exhaustion differentiation. Aim 2: Determine how Hobit expression regulates quiescence and cytotoxicity in transplanted CD8 T cells experiencing chronic antigen stimulation. We hypothesize that tuning Hobit expression can allow control over CD8 T cell activation during the chronic stimulation that occurs after HCT or after CAR-T therapy.