Chronic diseases like HIV, Hepatitis B and C, and cancers that evade the immune system continue to impact the lives of millions of patients worldwide causing high morbidity and mortality as well as significant economic burden. It is now evident that in these chronic diseases the development of dysfunctional or exhausted T cells contributes to their disease. It is significant that immune inhibitory pathways in T cells are shared across multiple pathogen types and species including murine, monkey, and humans. Therapeutic success targeting these inhibitory checkpoints using blocking antibodies can reinvigorate T cells and improve pathogen and tumor control in mice and patients.

These drugs are now standard treatment for cancer, but at present are only effective in a subset of patients, highlighting the need to identify additional inhibitory pathways that can be targeted to improve patient outcomes. We identified a new inhibitory checkpoint that promoted T cell exhaustion during chronic viral infection and during melanoma tumor development. Our long-term goal is to understand fundamental cellular and molecular mechanisms of T cell dysfunction. The rationale is that once we fully understanding these inhibitory pathways, we can develop effective therapeutics to reinvigorate the immune system and help more patients suffering from these diseases.