Our lab investigates the functional states of T cells, including T cell memory and exhaustion. Both are important factors in the body’s ability to fight disease. Exhaustion is a T cell’s loss of function following exposure to a chronic source of antigen, such as the antigen found on a tumor. In contrast, functional memory T cells are generated from an acute antigen exposure and these cells retain the ability to recognize the antigen again at a much later time and rapidly initiate an immune response against the disease or foreign agent.
In the context of cancer immunotherapy, you can see how the two states significantly affect the ability to use patients’ immune systems to fight cancer. We recently learned more about T cells by studying their behavior in Type 1 diabetes.
Type 1 diabetes, also called juvenile diabetes, is an autoimmune disease. Immune cells called CD8 T cells kill the insulin-producing islet cells in the pancreas.
We learned the T cells retain their ability to attack islet cells over successive generations. This biological “dual personality” means the T cells can copy and maintain this memory.
Our work investigating this mystery appeared in the journal Nature Immunology.
The activity of cells is governed by genetic and epigenetic regulation, control switches that give instructions to a cell. The epigenetic mechanisms include methylation. The process involves using methyl molecules to tag DNA at key points to suppress genetic activity. We compiled an epigenetic atlas of CD8 T cells to identify the programs and molecules that control cell development through methylation.
The atlas includes data on the pattern of distribution of a central epigenetic control mechanism across the genome of CD8 T cells. A key feature of the atlas was the creation of a multipotency index. The index lets investigators determine the epigenetic signatures that reveal the differentiation state of T cells.
Now that we know the role of epigenetic programming in CD8 T cell differentiation, we can look at therapies to induce immunological tolerance and protect islet cells. The multipotency index can also help predict the success of cancer immunotherapies that rely on engineering patient T cells to attack tumor cells. The epigenetic signature can be used to predict which individuals will be therapeutic responders versus non-responders to T cell-based therapies prior to the initiation of treatment.
We are currently working with our colleagues in Bone Marrow Transplantation and Cellular Therapy in applying this predictive index toward analysis of the ongoing CD19 CAR T cell protocol (SJCAR19). Additionally, now that we know several of the regulators of the exhaustion program, we are planning to use gene editing approaches to generate exhaustion-resistant T cells to improve longevity of current CAR T-cell therapies for the treatment of cancer.