Unraveling T Cell Dysfunction: from Co-Inhibitory Receptors to Molecular Programs

Immunology Interest Group Seminar Series In chronic diseases such as cancer and chronic viral infections, T cells acquire a dysfunctional state characterized by variable loss of effector functions. Dysfunctional T cells express multiple co-inhibitory receptors, such as CTLA-4 and PD-1, and blockade of these receptors has been harnessed to improve T cell responses and clinical outcome in multiple cancer indications. Unfortunately, the current therapies directed against CTLA-4 and PD-1 do not reach all patients and resistance to these therapies is increasing. This has prompted intense investigation into gaining a deeper understanding of the relationship of co-inhibitory receptors to the dysfunctional T cell state as well as achieving a more precise molecular definition of T cell dysfunction. To this end, we have investigated the cell extrinsic mechanisms that contribute to T cell dysfunction as well as the cell intrinsic gene programs that give rise to this T cell state. Through these studies we have uncovered extracellular signals that drive co-inhibitory receptor expression on T cells as well as important roles for co-inhibitory receptor expression on regulatory T cells in promoting T cell dysfunction. Importantly, we have uncovered a cell intrinsic role for zinc metabolism downstream of intracellular metallothioneins in driving T cell dysfunction. Through population and single-cell RNA profiling of wild type and metallothionein deficient T cells, we have identified a distinc...
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