Exhausted, or anergic T cells show up in increasing numbers in the aged immune system, or in an immune system worn down by persistent infections such as HIV. Most people are in fact infected by the persistent herpesvirus CMV by the time they are old, and this is thought to have a detrimental effect on the immune system, contributing to its collapse into immunosenescence. Exhausted T cells take up space that could be hosting useful cells, but are largely ineffective at their jobs. The direct approach to fixing this problem is to find ways to selectively destroy these cells, or destroy the entire immune system and then rebuild it from a patient's own cells, something that has been shown to cure autoimmunity, and is these days looking more practical for other uses now that the scientific community is making progress on side-effect-free alternatives to chemotherapy for that destruction. In this case, the researchers involved are more interested in reprogramming exhausted T cells, to see if their exhaustion can be removed. They make a solid attempt, but find it is more challenging than hoped:
Microbes that cause diseases like HIV, malaria, and hepatitis C exploit and often activate immune checkpoint pathways - cell surface receptors such as CTLA4 and PD-1 - to slow immune cells and prevent their elimination by the host. T cells that are supposed to clear an infection, instead, become "exhausted." The cell-surface receptors naturally act like brakes to tell the immune system to not react as strongly during normal situations and help the immune system avoid damaging healthy tissue or causing autoimmunity. Blocking PD-1 can reinvigorate exhausted T cells and improve control of chronic infections and cancer. However, whether blocking PD-1 can reprogram exhausted T cells into durable memory T cells is unclear. Researchers have now found that reinvigorating exhausted T cells in mice using a PD-L1 blockade caused very few T memory cells to develop. After the blockade, re-invigorated T cells became re-exhausted if antigen from the virus remained high, and failed to become memory T cells when the virus was cleared.
Epigenetics is the way chemical modifications to DNA and the proteins binding DNA determine which genes are expressed by a cell type. Epigenetic profiles can be highly stable and confer long-term identity to a cell. (In other words, the reason a liver cell stays a liver cell and doesn't become a lung cell is due largely to epigenetics since both liver and lung cells have the same genes.) "What these new findings on exhausted T cells tells us is that the unique epigenetic profile of exhausted T cells causes these cells to express a different overall set of genes compared to memory or effector T cells." However, this epigenetic pattern was only minimally changed following the PD-L1 blockade. This prevented these exhausted T cells from changing into the more protective effector or memory cell types. "We were surprised that the exhausted T cell epigenetic profile was not reprogrammed. Instead, the benefit we see after PD-1 pathway blockade is caused by only transient changes in gene expression that is not durable, rather than permanent epigenetic reprogramming." These findings suggested that exhausted T cells are a distinct lineage of T cells in and of themselves instead of just being effector or memory T cells restrained by checkpoint pathways. "We predicted that exhausted T cells would not have a distinct epigenetic profile but have the molecular flexibility to obtain immune memory. But we found that exhausted T cells are quite set in their ways. We think this shows that epigenetic fate inflexibility may limit current immunotherapies based on PD-1 checkpoint inhibitors."
Link: http://www.uphs.upen...2016/10/wherry/
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