CD8+ T lymphocytes are immune cells responsible for the clearance of virally-infected or tumor cells from the body. Exhaustion of these cells is a major barrier to effective clearance of chronic viral infection and cancer by the immune system. When T cells are continually stimulated with antigen, as in cancer or chronic infection, T cells enter this state of exhaustion, marked by loss of cytokine production, proliferative potential, and killing capacity. The ability to ameliorate or reverse T cell exhaustion holds great promise for the treatment of cancer, as blockade of cell surface molecules implicated in exhaustion has revolutionized treatment of various types of cancer. In particular, blockade of the PD-1 pathway has transformed cancer therapeutics with its ability to rejuvenate exhausted, cancer-specific CD8+ T cells. Unfortunately, not all patients respond to PD-1 blockade, making the discovery of alternative methods to stimulate exhausted cells an important field of research. Development of novel immunotherapies requires the definition of CD8+ T heterogeneity in chronic viral infections and cancer. Recent work in the laboratory of Rafi Ahmed and elsewhere has shown that Tcf-1+ CD8+ T cells sustain the antigen-specific response in chronic viral infection. Additionally, these cells are also responsible for the proliferative burst of T cells seen after PD-1 pathway blockade. My preliminary data show that in chronic viral infection, antigen-specific Tcf-1+ CD8+ T cells initially differentiate into a highly proliferative, cytotoxic, transitory state characterized by expression of Tim3 and lack of CD101. After continued antigen exposure, these CD101-Tim3+ cells convert into CD101+Tim3+ cells that are unable to divide and express effector molecules such as granzyme B and IFN?, even in the presence of continued antigen exposure. I hypothesize that halting CD8+ T cell differentiation into the CD101+ state may improve effector function of exhausted CD8+ T cells and bring additional cells into the immunotherapy-responsive pool. The goal of this project is three-fold. First, I will comprehensively determine the progressively dysfunctional states through which antigen-specific CD8+ T cells progress in chronic viral infection. Second, I will determine the biological function and therapeutic potential of two surface molecules associated with this differentiation pathway, CD101 and CD112R. Finally, this grant will allow the completion of my own postdoctoral training in the laboratory of Rafi Ahmed, PhD and facilitate my transition into an independent researcher studying new approaches to rejuvenate the CD8+ T cell response in chronic viral infections and cancer.
The immune system is responsible for the elimination of pathogens and cancer from the human body. This proposal studies a subset of immune cells, known as CD8+ T cells, which are responsible for killing cancer cells as well as host cells that are infected with intracellular pathogens. Here, we will research previously unexplored ways in which the CD8+ T cell response is inhibited in chronic viral infection and cancer.
