When continually stimulated, as occurs in persistent viral infections and cancer, T cells of the adaptive immune system become exhausted. This state is characterized by an inability to attack and kill pathogens and harmful cells. As with any other aspect of the immune system, however, exhaustion is not a well-defined and simple binary state, but rather a broad category that contains many different subtypes of exhausted cell, degrees of exhaustion, and distinct biochemistries contributing to exhaustion. Cellular biochemistry is complicated at every level.
Researchers want to find effective ways to reprogram T cells to exit exhaustion or resist the onset of exhaustion. This seems possible in principle, and a number of technology demonstrations exist to demonstrate that at least some manipulation of T cell exhaustion can be accomplished. Turning those initial research results into useful therapies is very different matter, of course. Today’s research materials report on new discovery that may help to make exhaustion less of a problem in cancer and persistent infection. The researchers have identified GFI1 as a regulator of the degree to which exhaustion prevents T cells from generating a useful response to pathogens and cancerous cells, and GFI1 inhibitors may prove to be a useful class of drug.
Reinvigorating exhausted T cells in cancer and chronic viral infections
Killer immune cells destroy cancer cells and cells infected by virus. However, in chronic viral infection and cancer, the killer cells often lapse into “exhausted” CD8+ T cells that no longer can stem disease. Exhausted CD8+ T cells are a complex population of subsets composed of progenitor cells and “effector-like” or “terminally exhausted” cells. Effector-like cells still retain some killer ability.
Researchers used mice infected with a chronic virus to describe four subsets in the population, including a previously under-described Ly108+CX3CR1+ subset that expresses low levels of Gfi1, while other established subsets have high expression. This Ly108+CX3CR1+ subset is transitory and develops to terminally exhausted cells and effector-like cells, which retain some tumor killing ability. This process depends on low levels of Gfi1.
“Considering Gfi1 downregulation is associated with the active differentiation of CD8+ T cell progenitors, we argue that transient and intermittent inhibition of Gfi1 with lysine-specific histone demethylase may facilitate the differentiation of progenitors to Ly108+CX3CR1+ cells and then to effector-like cells, thereby improving the control of chronic infections and tumors/”
Gfi1 controls the formation of effector-like CD8+ T cells during chronic infection and cancer
During chronic infection and tumor progression, CD8+ T cells lose their effector functions and become exhausted. These exhausted CD8+ T cells are heterogeneous and comprised of progenitors that give rise to effector-like or terminally-exhausted cells. The precise cues and mechanisms directing subset formation are incompletely understood. Here, we show that growth factor independent-1 (Gfi1) is dynamically regulated in exhausted CD8+ T cells.
During chronic LCMV Clone 13 infection, a previously under-described Ly108+CX3CR1+ subset expresses low levels of Gfi1 while other established subsets have high expression. Ly108+CX3CR1+ cells possess distinct chromatin profiles and represent a transitory subset that develops to effector-like and terminally-exhausted cells, a process dependent on Gfi1. Similarly, Gfi1 in tumor-infiltrating CD8+ T cells is required for the formation of terminally differentiated cells and endogenous as well as anti-CTLA-4-induced anti-tumor responses. Taken together, Gfi1 is a key regulator of the subset formation of exhausted CD8+ T cells.
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